This Article Free upon publication Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liang, C.-P. Articles by Tall, A. R. Search for Related Content PubMed PubMed Citation Articles by Liang, C.-P. Articles by Tall, A. R.

(Circulation Research. 2007;100:1546.)
© 2007 American Heart Association, Inc.

Reviews

The Macrophage at the Crossroads of Insulin Resistance and Atherosclerosis

Chien-Ping Liang, Seongah Han, Takafumi Senokuchi, Alan R. Tall

From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York.

Correspondence to Chien-Ping Liang, Division of Molecular Medicine, Department of Medicine, Columbia University, 630 West 168th St., New York, NY 10032. E-mail CL534{at}columbia.edu

This Review is part of a thematic series on the Atherosclerosis in Diabetes: Dyslipidemia vs Hyperglycemia, which includes the following articles:

Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques?

Recipes for Creating Animal Models of Diabetic Cardiovascular Disease

The Macrophage at the Crossroads of Insulin Resistance and Atherosclerosis

Lipids, glucose, and oxidative reactions in diabetes and atherosclerosis
Karin E. Bornfeldt Guest Editor

	Abstract

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
The macrophage has emerged as an important player in the pathogenesis of both atherosclerosis and insulin resistance. Cross-talk between inflammatory macrophages and adipocytes may be involved in insulin resistance in peripheral tissues. Defective insulin signaling in cells of the arterial wall including macrophages may promote the development of atherosclerosis. Insulin resistant macrophages are more susceptible to endoplasmic reticulum stress and apoptosis in response to various stimuli such as nutrient deprivation, free cholesterol loading, and oxidized LDL. Increased apoptosis of insulin resistant macrophages and impaired phagocytic clearance of apoptotic cells by insulin resistant macrophages in atherosclerotic lesions may lead to enhanced postapoptotic necrosis, larger lipid-rich cores, increased inflammation, and more complex vulnerable plaques.

Key Words: atherosclerosis • insulin resistance • diabetes mellitus • macrophages • apoptosis

	Introduction

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
The risk of atherosclerotic cardiovascular disease is increased 2- to 3-fold in type 2 diabetes mellitus¹ and metabolic syndrome.² In type 2 diabetes both insulin resistance and hyperglycemia may promote atherosclerosis and its complications,^3–5 while insulin resistance is likely a key underlying factor driving the complications of metabolic syndrome including atherosclerosis.⁶ Hyperinsulinemia is an independent risk factor for atherosclerosis in some but not all epidemiological studies.^7,8 Because hyperinsulinemia is often associated with other risk factors such as dyslipidemia, it may be difficult to segregate out independent effects of insulin resistance in such studies. An alternative view to the central role of insulin resistance is that in obesity and metabolic syndrome an inflammatory reaction in adipose and blood vessels drives atherosclerosis and its complications.⁹ These are not mutually exclusive concepts as inflammation may induce insulin resistance,^10,11 and as suggested below insulin resistance could lead to cellular events that provoke inflammatory responses.

Insulin resistance likely acts via dyslipidemia (increased VLDL and reduced HDL levels), hypertension, and a hypercoagulable state to accelerate atherosclerosis and its complications.^3,12 Dyslipidemia reflects both peripheral insulin resistance and increased flux of fatty acids to the liver, as well as direct effects of insulin signaling in hepatocytes, leading to increased secretion of VLDL.¹² The mechanisms of reduced HDL levels in metabolic syndrome are poorly understood but may in part reflect accelerated cholesteryl ester (CE) transfer protein–mediated transfer of CE from HDL to VLDL and consequent hypercatabolism of HDL particles. Insulin resistance in adipose tissue leads to increased synthesis of plasminogen activator inhibitor-1, contributing to a prothrombotic state.¹³ Vascular insulin resistance causes impaired nitric oxide–mediated arterial dilation¹⁴ and likely smooth muscle cell proliferation.¹⁵ In addition, recent results suggest that insulin resistance in macrophages may worsen atherosclerosis,¹⁶ and this will be the major topic of this review. These findings will also be examined in the context of a larger body of work implicating macrophage inflammatory responses in the induction of insulin resistance and atherosclerosis.

Insulin resistance is characterized both by hyperinsulinemia, as well as defective insulin signaling in a variety of different tissues. On a cellular level, hyperinsulinemia leads to increased degradation and reduced levels of insulin receptors (IRs; also named as CD220),¹⁷ and reduced levels of insulin receptor substrate proteins (IRSs) in various target tissues, such as liver, muscle, and vascular cells.^16,18,19 Thus, defective insulin signaling in cells is the sine qua non of insulin resistance. Many of the complications of insulin resistance reflect defective insulin signaling in cells. In addition, there may be mixed features of both insulin resistance and insulin sensitivity within the same cell or there may be varied insulin resistance and sensitivity in different organs. A prominent example of the picture of mixed insulin sensitivity and resistance is the liver in obese (ob/ob) mice, where insulin resistance leads to increased nuclear activity of the forkhead transcription factor FOXO1 and increased expression of gluconeogenic genes, whereas increased insulin signaling induces SREBP1c, enhanced expression of lipogenic genes, and increased VLDL secretion.^20,21 The mixed picture could reflect divergent pathways of insulin signaling or different thresholds for activation of lipogenic and gluconeogenic genes.

	The Insulin Signaling Pathway and Its Role in Monocytes and Macrophages

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
Monocyte-macrophages in human and experimental animal models are known for a wide spectrum of distinct phenotype, possibly reflecting their stages of differentiation and the nature of tissue microenvironments.²² Although different macrophage populations have been recently described to enter adipose tissue in obesity²³ or vascular lesions in atherosclerosis,²⁴ the functional significance is unknown and the relationship to studies on insulin signaling is uncertain. Thus we use the general terms monocytes or macrophages for discussion in this review.

Insulin Signaling
In insulin-responsive tissues, insulin signaling networks exert metabolic effects and also play a pivotal role in normal growth and development.²⁵ As an anabolic hormone, insulin enhances the synthesis and storage of carbohydrates, lipids, and proteins, and decreases degradation and release of these molecules from the tissues. At the cellular level, circulating insulin binds to its cognate receptor (IR) at the cell surface and activates its tyrosine kinase activity. This stimulates phosphorylation of receptor substrates and adaptor proteins, including IRS1/2, Gab-1, Cbl, Shc, and APS (adapter protein with a PH domain and an SH2 domain), on selected Tyr residues, thereby forming docking sites for further downstream effectors.²⁵ There are two major pathways involved in insulin-mediated metabolic and growth activities: those initiated by phosphatidylinositol 3-kinase (PI3K) and those downstream of mitogen activated protein (MAP) kinase signaling. The PI3K pathway is the main pathway mediating metabolic effects of insulin. Tyr-phosphorylated IRSs recruit and interact with the regulatory p85 subunit of PI3K, resulting in synthesis of phosphatidylinositol 3,4,5-phosphate (PIP₃) by the catalytic p110 subunit. The binding of downstream kinases PDK and AKT to PIP₃ causes their activation. AKT is known to mediate the responses of glucose transport, glycogen synthesis, protein synthesis, and antilipolytic effects of insulin. Some of these metabolic effects are mediated through AKT phosphorylation of FOXO transcription factors.^21,25 Tyr phosphorylated IRS proteins also interact with the Grb2-mSOS complex followed by activation of Ras and signaling via the MAP kinase pathway. Plasma membrane-associated Ras binds Raf kinase, which in turn stimulates MEK activity. MEK activates ERK1/2 and is involved in the regulation of mitogenesis or differentiation, and other cellular activities.

Insulin Signaling and Action in Monocyte-Macrophages
The insulin signaling cascade and its role in cell metabolism and growth have been widely characterized in classic insulin-sensitive mammalian organs such as liver, muscle, and fat.²⁵ However the literature on insulin signaling and action in macrophages is relatively sparse. Most insulin signaling molecules are expressed in macrophages. The notable exceptions are IRS1^16,26 and the glucose transporter GLUT-4.^27,28 The expression of other IRS isoforms in macrophages remains to be determined. Treatment of macrophages with insulin stimulates the IR/IRS2/PI3K/AKT signaling cascade,^{16,26,29–31} similar to its effects in canonical insulin-responsive cells. Less clear is the responses of the MAP kinase pathway to insulin in macrophages though it is known that the Ras/Raf/MEK/ERK pathway is active in these cells.³²

The biological functions of insulin signaling in macrophages remain largely unknown, but could involve support of viability, protein synthesis and secretion, and phagocytosis, and thus the overall role of the macrophage innate immunity. Early studies documented several effects of insulin on macrophage metabolism. In the glycolytic pathway insulin was found to increase hexokinase and citrate synthase activities in rat macrophages, while inhibiting glucose 6-phosphate dehydrogenase in the pentose phosphate pathway.³³ Although mouse macrophages express PI3K/AKT and Cbl/flotillin/Rho components, thought to be involved in insulin-stimulated glucose transport, insulin has no effects on 2-deoxy-D-glucose uptake by macrophages.¹⁶ Perhaps glucose transport in these GLUT-4–deficient cells is facilitated mainly by GLUT-1. Regarding macrophage innate immunity, hyperinsulinemia is known to increase phagocytic NADPH oxidase activity in human macrophages, possibly through protein kinase C, and to stimulate H₂O₂ production.³⁴ In rat macrophages, insulin can increase the activities of antioxidant enzymes such as Cu/Zn superoxide dismutase.³⁵ In addition, insulin has been reported to affect phagocytosis by macrophages.^36,37 Thus insulin may modulate macrophage carbohydrate metabolism, redox activity, and phagocytic capacity. It remains unclear whether insulin affects antigen processing and presentation in macrophages.

	Abnormal Functions in Insulin Resistant Macrophages

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
Macrophage Abnormalities in Diabetes
Monocyte-macrophages in type 2 diabetes and metabolic syndrome show some altered immune and inflammatory activities. For example, these macrophages have decreased phagocytosis of microbes.³⁸ The expression of inflammatory mediators such as interleukin (IL)-6 is increased in adipose tissue macrophages in obesity.³⁹ Macrophages of obese mice show an increase in oxidative stress.^40,41 In addition, monocytes from diabetic subjects exhibit enhanced adherence to the endothelium,^42,43 suggesting an increased ability of tissue infiltration under diabetic conditions. These abnormalities therefore may contribute to the development of systemic inflammation and insulin resistance associated with obesity and diabetes (see below).

Macrophages play a central role in mediating atherogenesis. In 70’s and 80’s, most studies used LDL and VLDL isolated from diabetic patients or diabetic animal models to examine lipoprotein metabolism in wild-type monocytes/macrophages. These studies showed increased association, degradation, and CE synthesis after incubation of macrophages with diabetic VLDL or LDL compared with lipoproteins from normal controls,⁴⁴ suggesting a role of diabetic lipoproteins in the acceleration of atherosclerosis in diabetes. The enhancement of uptake is likely related to altered composition and modification of these lipoproteins.⁴⁵

More recent studies addressed the defects of macrophages in diabetes relevant to the pathogenesis of atherosclerosis. For instance, there is some evidence for impairment of cholesterol efflux pathways in macrophages. In macrophages isolated from type 2 diabetic db/db or KKay mice, ABCG1 mediated cholesterol efflux to HDL (but not apo A-I) is reduced,⁴⁶ though no significant difference in efflux was found in ob/ob LDLR^–/– macrophages.^16,47 Some of the derangements (eg, aberrant expression of ABCG1) found in diabetes are attributable to hyperglycemia, whereas others appear to be related to distinct metabolic parameters such as insulin resistance.

Insulin Resistant Macrophages
Previous studies suggested an intimate association of reduced monocyte IR activity with systemic insulin resistance in human.⁴⁸ Monocyte-macrophages isolated from diabetic subjects and animal models show decreased surface expression and tyrosine kinase activity of IR^16,49,50 and diminished insulin-stimulated signaling of IRS2, PI3K, and AKT.^16,30,31 Thus macrophages in insulin-resistant states and diabetes are resistant to circulating insulin at the cellular level.

Recently we examined lipoprotein metabolism in insulin resistant macrophages from obese ob/ob mice and from IR knockout mice. Mice with a generalized inactivation of the IR die in the neonatal period from keto-acidosis,⁵¹ but viability can be rescued by expressing an IR transgene in the liver.⁵² Primary macrophages from ob/ob and transgenically rescued IR-deficient mice exhibit enhanced binding and uptake of modified LDL and elevated CE formation,¹⁶ suggesting that macrophage insulin resistance promotes uptake of atherogenic lipoproteins and foam cell formation. Conversely, in vivo the PPAR- activator rosiglitazone, a insulin sensitizing agent, reverses abnormal macrophage phenotype with improved insulin signaling and decreased modified LDL binding in macrophages from treated ob/ob LDLR^–/– mice.¹⁶ These findings thus suggest macrophage insulin resistance as a key parameter potentially determining atherosclerotic responses in diabetes and metabolic syndrome.

Mechanisms of CD36 and SR-A Induction
Scavenger receptors CD36 and SR-A (CD204) are responsible for about 75% to 90% of the uptake of modified lipoproteins by macrophages in culture.⁵³ Altered macrophage lipoprotein metabolism in insulin-resistant states and diabetes was shown to reflect increased surface expression of CD36 and/or SR-A.^{16,46,54–56} In insulin resistant macrophages, we found both CD36 and SR-A are posttranscriptionally upregulated¹⁶ (Figure 1), though distinct mechanisms may underlie the abnormalities of each receptor. Increased expression of CD36 is associated with enhanced recycling of the receptor to the cell surface, and is related to defective macrophage PI3K activity.¹⁶ The induction of SR-A is secondary to the unfolded protein response (UPR) which is exaggerated in insulin resistant macrophages (see below).³⁰ Elevated expression of CD36 on the surface of human monocyte-macrophages and in arterial foam cells was reported in diabetic subjects.^54,55 Alternative mechanisms thought to be related to glucose-regulated CD36 protein translation^54,55 and SR-A mRNA and protein expression⁵⁶ in human cells have been proposed. Such an effect of hyperglycemia on CD36 and SR-A expression was not observed in C57BL/6J mouse macrophages.^16,30 Therefore, macrophage CD36 and SR-A may be posttranscriptionally induced in insulin-resistant states and diabetes, potentially involving several different mechanisms.

View larger version (46K): [in this window] [in a new window]   Figure 1. A schematic representation of the mechanisms for increased formation of lipid-rich necrotic cores within atherosclerotic lesions in diabetes and metabolic syndrome. Defective macrophage insulin signaling induces expression of scavenger receptors SR-A and CD36 and promotes modified LDL uptake. Trafficking of lipoprotein free cholesterol after lysosomal hydrolysis to the ER increases ER cholesterol contents. The heightened ER stress triggered by cholesterol accumulation in turn leads to an increase in SR-A expression and a decrease in IR signaling. These amplified responses cause increased susceptibility of insulin resistant macrophages to apoptosis induced by modified lipoproteins. Enhanced macrophage apoptosis and impaired phagocytosis by insulin resistant macrophages in the plaques may augment lipid core formation and inflammatory responses as a result of increased macrophage necrosis. IR indicates insulin receptor; SR-A, scavenger receptor class A; FC, free cholesterol; ER, endoplasmic reticulum; m, macrophage.

	Macrophage Insulin Resistance, Apoptosis, and Advanced Lesion Formation

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
Insulin Resistant Macrophages and Atherosclerotic Lesion Complexity
Our studies¹⁶ suggested a potential proatherogenic role of defective macrophage insulin signaling in diabetic atherosclerosis. Two animal studies with extreme cellular insulin resistance have been performed to directly test this hypothesis. In the first study, we performed bone marrow transplantation from transgenically rescued IR knockout mice into LDLR^–/– mice fed Western diet containing 0.2% cholesterol.³⁰ Plasma levels of lipoproteins, insulin or glucose were similar in animals transplanted with IR^+/+ or IR^–/– bone marrow. No significant difference in the area of early foam cell lesions was found in mice receiving IR-deficient bone marrow. However, IR^–/– bone marrow recipients developed larger, more complex lesions at a later stage, accompanied by a pronounced increase in apoptotic cells and necrotic core formation. Examination of lesion cellularity showed that macrophages were the predominant cell type, occupying about 50% of lesion area. Lipid-rich necrotic cores in advanced atherosclerotic lesions arise from macrophages that have undergone either necrotic or apoptotic cell death.

Insulin Resistant Macrophages and Inflammation
In a second study, J. Baumgartl et al used LysM Cre to inactivate the floxed IR gene in macrophages in apoE^–/– mice.⁵⁷ These mice were fed a diet containing a very high cholesterol content (5%) and showed reduced areas of aortic lesions. Plaque formation in apoE^–/– transplanted with fetal liver cells of IRS2^–/–apoE^–/– mice was also decreased. In vitro IR^–/–apoE^–/– macrophages when chronically challenged with lipopolysaccharide exhibited reduced secretion of proinflammatory IL-6 without significant changes in the release of TNF-, possibly reflecting some selective defects in toll-like receptor signaling or NF-B activity in mutant cells. This study suggests a protective role of impaired insulin signaling in myeloid lineage cells in atherosclerosis, related to a reduced inflammatory response.

The reasons for the somewhat disparate results of these two studies^30,57 are not completely clear. The characterization of lesions was performed in different regions and at different stages of plaque development. Perhaps more importantly, different atherogenic diets were used in these studies, ie, the Western-type diet containing 0.2% cholesterol (0.15% added and 0.05% from fat)³⁰ versus a diet supplemented with 5% cholesterol.⁵⁷ A high dietary cholesterol content has been shown to cause a profound hepatic inflammatory response.⁵⁸ Thus, it is possible that a decreased inflammatory response of insulin resistant macrophages could ameliorate the atherosclerotic response in animals fed a very high cholesterol diet, whereas enhanced apoptosis of insulin resistant macrophages may worsen advanced lesions in animals fed the Western type diet. Our results are also consistent with a recent study in apoE^–/– mice transplanted with ATM (Ataxia Telangiectasia Mutated)-deficient bone marrow. ATM^–/– macrophages show reduced IRS2 expression and elevated c-Jun N-terminal kinase (JNK) activity.⁵⁹ When fed the Western diet, apoE^–/– mice receiving ATM^–/– bone marrow exhibit increased aortic lesion area.⁵⁹

Diabetic patients are known to exhibit more advanced lesion development and increased acute coronary syndrome. In this context, our results³⁰ are consistent with recent autopsy data⁶⁰ from human type 2 diabetics who show increased regions of necrotic core and enhanced macrophage apoptosis in their atherosclerotic lesions, apparently predisposing to plaque rupture, coronary thrombosis, and sudden death. Thus our work demonstrates a causal link between macrophage insulin resistance, death of macrophage foam cells, and necrotic core formation in advanced atherosclerotic plaques in diabetes and metabolic syndrome, and this may lead to increased vulnerability of the plaques in these disease states.

	Potential Mechanisms: Role of Macrophage Apoptosis and Phagocytosis

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
The features in advanced lesions in IR^–/– bone marrow recipients³⁰ may result from adverse enhanced macrophage apoptosis and/or impaired phagocytic clearance of apoptotic macrophages (Figure 1). Insulin exerts antiapoptotic effects in macrophages, endothelial cells, and smooth muscle cells in vitro.^61–63 During phagocytosis of apoptotic cells, both PI3K/AKT^64,65 and MEK/ERK^65–67 signaling cascades in normal phagocytic macrophages are involved. Further research is needed to determine whether engulfment of apoptotic cells by macrophages is altered in type 2 diabetes.

Apoptosis, Phagocytosis, and Atherosclerosis In Vivo
The relationship of macrophage apoptosis to atherosclerosis is complex.⁶⁸ Results of bone marrow transplantation from mice deficient in AIM (apoptosis inhibitor expressed by macrophages)⁶⁹ or BAX⁷⁰ suggest that in early fatty streak lesions there is efficient macrophage-mediated clearance of apoptotic cells. As plaques advance to the later stages of development, the responses to apoptosis seem different. This is supported by the studies with tissue inhibitor of metalloproteinase-2 gene transfer⁷¹ and IR-deficient transplantation.³⁰

The role of macrophage phagocytic defects in advanced plaque formation in vivo is largely unexplored. In one study,⁷² macrophage-mediated phagocytosis of apoptotic cells appears impaired in advanced human and rabbit atherosclerotic lesions. LDLR^–/– mice transplanted with transglutaminase 2–deficient bone marrows show increased aortic lesion regions along with defective phagocytosis of apoptotic cells by macrophages.⁷³ In all, these data suggest that enhanced apoptosis and/or failed phagocytosis can be important contributors to the progression or complications of atherosclerotic plaques.

Insulin Resistant Macrophages and Cholesterol-Induced Apoptosis In Vitro
Two different pathways relevant to macrophage apoptosis in atherosclerosis have been described, one involving the uptake of oxidized cholesterol in LDL and another initiated by loading with lipoprotein free cholesterol (FC).^68,74 Our results indicate an increase in susceptibility of IR-deficient macrophages to apoptosis triggered by oxidized LDL or FC loading in vitro.³⁰ FC-induced apoptosis in macrophages requires a "multi-hit" mechanism involving both FC loading and ligation of SR-A.⁷⁵ Thus an increase in SR-A in IR^–/– macrophages predisposes to apoptosis both by enhanced uptake of modified LDL and by providing a stronger "second hit" related to SR-A engagement (Figure 1). Apart from cholesterol accumulation, macrophage ATP depletion, a feature of advanced atherosclerotic plaques,⁷⁶ may also contribute to apoptosis. Indeed IR-deficient macrophages are more susceptible to apoptosis induced by glucose deprivation.³⁰ Overall our findings are consistent with the idea of increased susceptibility to apoptosis of IR^–/– macrophage foam cells in the lesions.

Cholesterol Accumulation, ER Stress, and Atherosclerosis In Vivo
In vitro FC loading promotes the UPR⁷⁷ and eventually leads to apoptosis as a result of CHOP induction and SR-A engagement.^75,77 The UPR is an adaptive program that assists cells to withstand endoplasmic reticulum (ER) stress such as conditions produced by protein overload and misfolding in the ER, nutrient deprivation, or pathogen infection.⁷⁸ While this adaptive response may facilitate recovery from stress, it can also induce apoptosis if stressful stimuli continue or if there are additional insults. Persistent imbalances of ER stress and UPR in the arterial wall may be relevant to atherogenesis or lesion progression. For example, several markers of ER stress including CHOP are found in atherosclerotic plaques.^77,79 Decreased NPC1-mediated cholesterol trafficking to the ER is associated with fewer apoptotic macrophages and smaller acellular lipid regions in advanced aortic lesions, as shown in NPC1^+/–apoE^–/– versus NPC1^+/+apoE^–/– mice.⁸⁰ Therefore, sustained ER stress in vivo appears to promote macrophage death and advanced lesion formation.

Mechanisms of Macrophage Survival Following Cholesterol Overload
PI3K/AKT and MEK/ERK are both induced in response to ER stress produced by FC, thapsigargin, or tunicamycin treatments,^30,81,82 thereby counteracting ER stress–induced apoptosis as survival mechanisms.⁸² Primary IR^–/– macrophages show modestly increased ER stress, and reduced AKT activity on serum starvation.³⁰ After FC overload, the AKT response in these cells is attenuated and short-lived with more robust induction of CHOP and apoptosis.³⁰

Potential Roles of AKT, Autophagy, and SR-A Signaling in Insulin Resistant Cells
Several potential mechanisms can explain increased apoptosis of IR^–/– macrophages by FC loading (Figure 2). First, impaired induction of AKT appears to predispose IR-deficient macrophages to death. Some AKT substrates have been implicated as important in cell survival. For example, AKT directly phosphorylates and inactivates the proapoptotic protein BAD.⁸³ Another target the FOXO transcription factor is known to induce apoptosis in lymphocytes and neurons.⁸⁴ AKT may promote survival by nuclear exclusion of FOXO through phosphorylation. Alternatively, AKT can phosphorylate and stimulate p300/CBP acetyltransferase,^85,86 which in turn may inhibit FOXO activity via acetylation.⁸⁷ Macrophage FC loading leads to nuclear translocation of NF-B RelA/p65.⁸¹ Genetic ablation of p65 increases susceptibility to ER stress–induced apoptosis.⁸⁸ AKT reportedly activates NF-B activity through phosphorylation^89,90 or p300-mediated acetylation.⁸⁶ Inhibition or knockdown of AKT substrate GSK3 rescues ER stress–induced apoptosis.⁹¹ GSK3 activity is suppressed by AKT phosphorylation. Thus abnormal activity of a variety of different AKT substrates in response to ER stress in lipid-laden IR^–/– macrophages could result in enhanced apoptosis.

View larger version (45K): [in this window] [in a new window]   Figure 2. A working model of increased lesional apoptosis during the development of atherosclerotic plaques in insulin-resistant states. Cellular insulin resistance in cells of the arterial wall including macrophages promotes moderate ER stress responses and predisposes to apoptosis in the lesion environment. Under sustained stress conditions such as free cholesterol overload or nutrient deprivation, these cells exhibit attenuated and short-lived responses of AKT and perhaps MEK with more robust induction of apoptosis. SR-A–mediated proapoptotic signaling, possibly through inhibiting TLR-4/IRF3 pathway, may also contribute to apoptotic death of macrophages. Induction of cellular ER stress can further impair IRS signaling by activating JNK signaling and causing serine phosphorylation of IRS proteins.

Second, as noted above, FC loading induces macrophage MEK/ERK signaling.⁸¹ Activation of MAP kinase pathways as a cellular protection against apoptosis can occur through multiple mechanisms.⁹² A potential role of this cascade in preventing FC-induced cell death and in causing the defects in IR^–/– macrophage survival remains to be evaluated.

Third, ER stress induces autophagy, a regulated process of lysosome-mediated degradation of cellular proteins and organelles, promoting cell survival.^93,94 IRS2 activation is required for autophagy-mediated clearance of accumulated mutant protein aggregates.⁹⁵ Inactivation of autophagy genes, including Beclin 1 which is expressed in human atherosclerotic lesions,⁹⁶ triggers apoptosis.^93,97 Therefore it is plausible that a defect in autophagy in IR-deficient macrophages after FC loading or nutrient deprivation contributes to more cell death.

Fourth, SR-A engagement is required for FC-induced apoptosis in macrophages.^30,75 ER stress alone cannot trigger death unless SR-A is ligated, suggesting a role of SR-A signaling events in driving stressed cells toward apoptosis. Recently, SR-A–mediated suppression of antiapoptotic TLR-4/IRF3/interferon ß signaling cascade was shown to be indispensable for promoting death of ER-stressed macrophages.⁹⁸ Treatment of human monocytes with interferon ß leads to activation of PI3K/AKT.⁹⁹ Thus the contribution of inhibitory actions on the survival branch of TLR-4 signaling by SR-A ligation to increased apoptosis of FC-engorged IR^–/– macrophages needs to be further analyzed.

	The Role of Macrophages and Inflammation in Insulin Resistance

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
Proinflammatory cytokines derived from adipose tissue have a role in the pathogenesis of insulin resistance in metabolic syndrome.^10,11 Adipose tissue contains adipocytes and resident macrophages, both of which can be the sources of cytokine production. Recent studies have demonstrated increased accumulation of macrophages in adipose tissue of obese animals and humans, and have suggested they may have a direct role in the development of insulin resistance.^100,101 Adipose tissue and perhaps muscle macrophages can secrete proinflammatory cytokines, thereby promoting cellular insulin resistance in fat, muscle, and liver.^102–106 Fatty acids have been shown to activate TLR-4 and act via NF-B to induce insulin resistance.^107,108 The myeloid cell-specific knockout of IKKß results in increased macrophage inflammatory responses and peripheral and hepatic insulin resistance.¹⁰⁵ Thus, it is possible that fatty acids released from adipocytes act in a paracrine fashion to trigger TLR-4–mediated, NF-B–dependent inflammatory responses in macrophages. Subsequently, cytokines such as TNF- and IL-6 released from the macrophages may induce cellular insulin resistance in adipocytes or muscle cells by activating JNK signaling pathways and causing serine phosphorylation of IRS1/2.^107,109 Therefore, the paracrine cross-talk between macrophages and adipocytes can promote insulin resistance in obesity and metabolic syndrome. Consistent with this model, TLR-4 is expressed in macrophages and other cell types in atheromas,^110,111 and activation of TLR-4 signaling (eg, by fatty acids) in these cells may cause macrophage insulin resistance through direct stimulation of the macrophage TLR-4/JNK cascade¹¹² or via cytokine-mediated autocrine effects on macrophage JNKs.^109,113 In addition to the TLR-4 pathway, excess accumulation of fatty acids or their metabolites in insulin responsive cells or tissues in obesity may also impair insulin signaling and action by protein kinase C or oxidative stress.¹¹⁴

	Conclusions

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
Individuals with diabetes and metabolic syndrome have a higher risk of developing atherosclerosis and vascular complications. Experimental evidence presented in this review suggests that the emerging interplay between cellular insulin resistance, persistent ER stress, and apoptotic death in cells of the arterial wall may be a common denominator in the development of macrovascular complications in type 2 diabetes (Figures 1 and 2). Pharmacological therapies and management directed at abnormalities associated with insulin resistance and ER stress can likely reduce the burden of excess coronary events in diabetes and metabolic syndrome. Medications currently in use that improve peripheral insulin sensitivity include thiazolidinediones (eg, pioglitazone, rosiglitazone) and biguanides (metformin). Several human studies suggested antiatherogenic benefit of thiazolidinediones in diabetes, as revealed by the changes in carotid artery intimal medial thickness or in features of carotid atherosclerotic plaques in treated versus placebo diabetic patients.^115–117 However, in another study, rosiglitazone treatment may be accompanied by an increase in some adverse cardiovascular outcomes, possibly related to effects of PPAR- activation on the vasculature and heart independent of atherosclerosis.¹¹⁸

In mouse models of diabetes and obesity, induction of hepatic ER stress is associated with decreased insulin signaling in the liver.¹¹⁹ Oral administration to these animals of chemical chaperones, which alleviate cellular ER stress, leads to an improvement of systemic and hepatic insulin sensitivity accompanied by attenuated ER stress.¹²⁰ Only limited information is available to date regarding direct action on macrophages of these chaperone agents. For example, trimethylamine oxide and tauroursodeoxycholic acid were shown to stimulate phagocytosis by macrophages or Kupffer cells.^121,122 4-phenylbutyrate (also a deacetylase inhibitor) can rescue cells of various types from ER stress–induced apoptosis.^123,124 Two chaperones (tauroursodeoxycholic acid and 4-phenylbutyrate) are used in the treatment of other disorders. Their efficacy in the treatment and prevention of atherosclerosis in diabetes and metabolic syndrome remains to be assessed.

	Acknowledgments

 
We thank Drs Ira Tabas and Domenico Accili for many helpful discussions and insights, and Dr Andreas W. Jehle and Suzhao Li for comments on the manuscript.

Sources of Funding

This work was supported by National Institutes of Health Grant HL22682.

Disclosures

None.

	Footnotes

 
Original received December 8, 2006; resubmission received March 15, 2007; accepted March 28, 2007.

	References

Top Abstract Introduction The Insulin Signaling Pathway... Abnormal Functions in Insulin... Macrophage Insulin Resistance,... Potential Mechanisms: Role of... The Role of Macrophages... Conclusions References

 
1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339: 229–234.[Abstract/Free Full Text]

2. Malik S, Wong ND, Franklin SS, Kamath TV, L’Italien GJ, Pio JR, Williams GR. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation. 2004; 110: 1245–1250.[Abstract/Free Full Text]

3. Plutzky J, Viberti G, Haffner S. Atherosclerosis in type 2 diabetes mellitus and insulin resistance: mechanistic links and therapeutic targets. J Diabetes Complications. 2002; 16: 401–415.[CrossRef][Medline] [Order article via Infotrieve]

4. Renard CB, Kramer F, Johansson F, Lamharzi N, Tannock LR, von Herrath MG, Chait A, Bornfeldt KE. Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest. 2004; 114: 659–668.[CrossRef][Medline] [Order article via Infotrieve]

5. Vikramadithyan RK, Hu Y, Noh HL, Liang CP, Hallam K, Tall AR, Ramasamy R, Goldberg IJ. Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice. J Clin Invest. 2005; 115: 2434–2443.[CrossRef][Medline] [Order article via Infotrieve]

6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988; 37: 1595–1607.[Abstract]

7. Pyorala K. Hyperinsulinaemia as predictor of atherosclerotic vascular disease: epidemiological evidence. Diabete Metab. 1991; 17: 87–92.[Medline] [Order article via Infotrieve]

8. Lehto S, Ronnemaa T, Pyorala K, Laakso M. Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with Type II diabetes. Diabetologia. 2000; 43: 148–155.[CrossRef][Medline] [Order article via Infotrieve]

9. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.[Free Full Text]

10. Hotamisligil GS, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes. 1994; 43: 1271–1278.[Abstract]

11. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116: 1793–1801.[CrossRef][Medline] [Order article via Infotrieve]

12. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2000; 106: 453–458.[Medline] [Order article via Infotrieve]

13. Juhan-Vague I, Alessi MC, Morange PE. Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity. Ann Med. 2000; 32 Suppl 1: 78–84.[Medline] [Order article via Infotrieve]

14. Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR. The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest. 2003; 111: 1373–1380.[CrossRef][Medline] [Order article via Infotrieve]

15. Kubota T, Kubota N, Moroi M, Terauchi Y, Kobayashi T, Kamata K, Suzuki R, Tobe K, Namiki A, Aizawa S, Nagai R, Kadowaki T, Yamaguchi T. Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury. Circulation. 2003; 107: 3073–3080.[Abstract/Free Full Text]

16. Liang CP, Han S, Okamoto H, Carnemolla R, Tabas I, Accili D, Tall AR. Increased CD36 protein as a response to defective insulin signaling in macrophages. J Clin Invest. 2004; 113: 764–773.[CrossRef][Medline] [Order article via Infotrieve]

17. Knutson VP, Donnelly PV, Balba Y, Lopez-Reyes M. Insulin resistance is mediated by a proteolytic fragment of the insulin receptor. J Biol Chem. 1995; 270: 24972–24981.[Abstract/Free Full Text]

18. Kerouz NJ, Horsch D, Pons S, Kahn CR. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest. 1997; 100: 3164–3172.[Medline] [Order article via Infotrieve]

19. Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999; 104: 447–457.[Medline] [Order article via Infotrieve]

20. Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell. 2000; 6: 77–86.[CrossRef][Medline] [Order article via Infotrieve]

21. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003; 423: 550–555.[CrossRef][Medline] [Order article via Infotrieve]

22. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005; 5: 953–964.[CrossRef][Medline] [Order article via Infotrieve]

23. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007; 117: 175–184.[CrossRef][Medline] [Order article via Infotrieve]

24. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007; 117: 185–194.[CrossRef][Medline] [Order article via Infotrieve]

25. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7: 85–96.[CrossRef][Medline] [Order article via Infotrieve]

26. Welham MJ, Bone H, Levings M, Learmonth L, Wang LM, Leslie KB, Pierce JH, Schrader JW. Insulin receptor substrate-2 is the major 170-kDa protein phosphorylated on tyrosine in response to cytokines in murine lymphohemopoietic cells. J Biol Chem. 1997; 272: 1377–1381.[Abstract/Free Full Text]

27. Malide D, Davies-Hill TM, Levine M, Simpson IA. Distinct localization of GLUT-1, -3, and -5 in human monocyte-derived macrophages: effects of cell activation. Am J Physiol. 1998; 274: E516–E526.[Medline] [Order article via Infotrieve]

28. Fu Y, Maianu L, Melbert BR, Garvey WT. Facilitative glucose transporter gene expression in human lymphocytes, monocytes, and macrophages: a role for GLUT isoforms 1, 3, and 5 in the immune response and foam cell formation. Blood Cells Mol Dis. 2004; 32: 182–190.[CrossRef][Medline] [Order article via Infotrieve]

29. Grunberger G, Zick Y, Gorden P. Defect in phosphorylation of insulin receptors in cells from an insulin-resistant patient with normal insulin binding. Science. 1984; 223: 932–934.[Abstract/Free Full Text]

30. Han S, Liang CP, DeVries-Seimon T, Ranalletta M, Welch CL, Collins-Fletcher K, Accili D, Tabas I, Tall AR. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab. 2006; 3: 257–266.[CrossRef][Medline] [Order article via Infotrieve]

31. Hartman ME, O’Connor JC, Godbout JP, Minor KD, Mazzocco VR, Freund GG. Insulin receptor substrate-2-dependent interleukin-4 signaling in macrophages is impaired in two models of type 2 diabetes mellitus. J Biol Chem. 2004; 279: 28045–28050.[Abstract/Free Full Text]

32. Buscher D, Hipskind RA, Krautwald S, Reimann T, Baccarini M. Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. Mol Cell Biol. 1995; 15: 466–475.[Abstract]

33. Rosa LF, Cury Y, Curi R. Effects of insulin, glucocorticoids and thyroid hormones on the activities of key enzymes of glycolysis, glutaminolysis, the pentose-phosphate pathway and the Krebs cycle in rat macrophages. J Endocrinol. 1992; 135: 213–219.[Abstract/Free Full Text]

34. Fortuno A, San Jose G, Moreno MU, Beloqui O, Diez J, Zalba G. Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. Diabetes. 2006; 55: 209–215.[Abstract/Free Full Text]

35. Pereira B, Rosa LF, Safi DA, Bechara EJ, Curi R. Hormonal regulation of superoxide dismutase, catalase, and glutathione peroxidase activities in rat macrophages. Biochem Pharmacol. 1995; 50: 2093–2098.[CrossRef][Medline] [Order article via Infotrieve]

36. Ghezzo F, Garbarino G, Ioverno L. Insulin modulates human mononuclear adherent cell fibrinolytic and phagocytic activities. Scand J Haematol. 1983; 30: 379–383.[Medline] [Order article via Infotrieve]

37. Bar RS, Kahn CR, Koren HS. Insulin inhibition of antibody-dependent cytoxicity and insulin receptors in macrophages. Nature. 1977; 265: 632–635.[CrossRef][Medline] [Order article via Infotrieve]

38. Plotkin BJ, Paulson D, Chelich A, Jurak D, Cole J, Kasimos J, Burdick JR, Casteel N. Immune responsiveness in a rat model for type II diabetes (Zucker rat, fa/fa): susceptibility to Candida albicans infection and leucocyte function. J Med Microbiol. 1996; 44: 277–283.[Abstract/Free Full Text]

39. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007; 56: 16–23.[Abstract/Free Full Text]

40. Li SL, Reddy MA, Cai Q, Meng L, Yuan H, Lanting L, Natarajan R. Enhanced proatherogenic responses in macrophages and vascular smooth muscle cells derived from diabetic db/db mice. Diabetes. 2006; 55: 2611–2619.[Abstract/Free Full Text]

41. Lee FY, Li Y, Yang EK, Yang SQ, Lin HZ, Trush MA, Dannenberg AJ, Diehl AM. Phenotypic abnormalities in macrophages from leptin-deficient, obese mice. Am J Physiol. 1999; 276: C386–394.[Medline] [Order article via Infotrieve]

42. Bouma G, Lam-Tse WK, Wierenga-Wolf AF, Drexhage HA, Versnel MA. Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin. Diabetes. 2004; 53: 1979–1986.[Abstract/Free Full Text]

43. Carantoni M, Abbasi F, Chu L, Chen YD, Reaven GM, Tsao PS, Varasteh B, Cooke JP. Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM. Diabetes Care. 1997; 20: 1462–1465.[Abstract]

44. Kraemer FB, Chen YD, Lopez RD, Reaven GM. Effects of noninsulin-dependent diabetes mellitus on the uptake of very low density lipoproteins by thioglycolate-elicited mouse peritoneal macrophages. J Clin Endocrinol Metab. 1985; 61: 335–342.[Abstract/Free Full Text]

45. Lopes-Virella MF, Virella G. Modified lipoproteins, cytokines and macrovascular disease in non-insulin-dependent diabetes mellitus. Ann Med. 1996; 28: 347–354.[Medline] [Order article via Infotrieve]

46. Mauldin JP, Srinivasan S, Mulya A, Gebre A, Parks JS, Daugherty A, Hedrick CC. Reduction in ABCG1 in Type 2 diabetic mice increases macrophage foam cell formation. J Biol Chem. 2006; 281: 21216–21224.[Abstract/Free Full Text]

47. Mertens A, Verhamme P, Bielicki JK, Phillips MC, Quarck R, Verreth W, Stengel D, Ninio E, Navab M, Mackness B, Mackness M, Holvoet P. Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation. 2003; 107: 1640–1646.[Abstract/Free Full Text]

48. Frittitta L, Grasso G, Munguira ME, Vigneri R, Trischitta V. Insulin receptor tyrosine kinase activity is reduced in monocytes from non-obese normoglycaemic insulin-resistant subjects. Diabetologia. 1993; 36: 1163–1167.[CrossRef][Medline] [Order article via Infotrieve]

49. Comi RJ, Grunberger G, Gorden P. Relationship of insulin binding and insulin-stimulated tyrosine kinase activity is altered in type II diabetes. J Clin Invest. 1987; 79: 453–462.[Medline] [Order article via Infotrieve]

50. Naidoo C, Jialal I, Dunn RD, Govender T, Joubert SM. Insulin binding to circulating monocytes and erythrocytes in patients with non-insulin-dependent diabetes in the young. Diabetes Res. 1987; 4: 35–38.[Medline] [Order article via Infotrieve]

51. Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet. 1996; 12: 106–109.[CrossRef][Medline] [Order article via Infotrieve]

52. Okamoto H, Nakae J, Kitamura T, Park BC, Dragatsis I, Accili D. Transgenic rescue of insulin receptor-deficient mice. J Clin Invest. 2004; 114: 214–223.[CrossRef][Medline] [Order article via Infotrieve]

53. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, Rhee JS, Silverstein R, Hoff HF, Freeman MW. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002; 277: 49982–49988.[Abstract/Free Full Text]

54. Griffin E, Re A, Hamel N, Fu C, Bush H, McCaffrey T, Asch AS. A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation. Nat Med. 2001; 7: 840–846.[CrossRef][Medline] [Order article via Infotrieve]

55. Sampson MJ, Davies IR, Braschi S, Ivory K, Hughes DA. Increased expression of a scavenger receptor (CD36) in monocytes from subjects with Type 2 diabetes. Atherosclerosis. 2003; 167: 129–134.[CrossRef][Medline] [Order article via Infotrieve]

56. Fukuhara-Takaki K, Sakai M, Sakamoto Y, Takeya M, Horiuchi S. Expression of class A scavenger receptor is enhanced by high glucose in vitro and under diabetic conditions in vivo: one mechanism for an increased rate of atherosclerosis in diabetes. J Biol Chem. 2005; 280: 3355–3364.[Abstract/Free Full Text]

57. Baumgartl J, Baudler S, Scherner M, Babaev V, Makowski L, Suttles J, McDuffie M, Tobe K, Kadowaki T, Fazio S, Kahn CR, Hotamisligil GS, Krone W, Linton M, Bruning JC. Myeloid lineage cell-restricted insulin resistance protects apolipoproteinE-deficient mice against atherosclerosis. Cell Metab. 2006; 3: 247–256.[CrossRef][Medline] [Order article via Infotrieve]

58. Vergnes L, Phan J, Strauss M, Tafuri S, Reue K. Cholesterol and cholate components of an atherogenic diet induce distinct stages of hepatic inflammatory gene expression. J Biol Chem. 2003; 278: 42774–42784.[Abstract/Free Full Text]

59. Schneider JG, Finck BN, Ren J, Standley KN, Takagi M, Maclean KH, Bernal-Mizrachi C, Muslin AJ, Kastan MB, Semenkovich CF. ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. Cell Metab. 2006; 4: 377–389.[CrossRef][Medline] [Order article via Infotrieve]

60. Burke AP, Kolodgie FD, Zieske A, Fowler DR, Weber DK, Varghese PJ, Farb A, Virmani R. Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler Thromb Vasc Biol. 2004; 24: 1266–1271.[Abstract/Free Full Text]

61. Iida KT, Suzuki H, Sone H, Shimano H, Toyoshima H, Yatoh S, Asano T, Okuda Y, Yamada N. Insulin inhibits apoptosis of macrophage cell line, THP-1 cells, via phosphatidylinositol-3-kinase-dependent pathway. Arterioscler Thromb Vasc Biol. 2002; 22: 380–386.[Abstract/Free Full Text]

62. Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S. Insulin-mediated stimulation of protein kinase Akt: A potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol. 2000; 20: 402–409.[Abstract/Free Full Text]

63. Nakazawa T, Chiba T, Kaneko E, Yui K, Yoshida M, Shimokado K. Insulin signaling in arteries prevents smooth muscle apoptosis. Arterioscler Thromb Vasc Biol. 2005; 25: 760–765.[Abstract/Free Full Text]

64. Leverrier Y, Okkenhaug K, Sawyer C, Bilancio A, Vanhaesebroeck B, Ridley AJ. Class I phosphoinositide 3-kinase p110beta is required for apoptotic cell and Fcgamma receptor-mediated phagocytosis by macrophages. J Biol Chem. 2003; 278: 38437–38442.[Abstract/Free Full Text]

65. Reddy SM, Hsiao KH, Abernethy VE, Fan H, Longacre A, Lieberthal W, Rauch J, Koh JS, Levine JS. Phagocytosis of apoptotic cells by macrophages induces novel signaling events leading to cytokine-independent survival and inhibition of proliferation: activation of Akt and inhibition of extracellular signal-regulated kinases 1 and 2. J Immunol. 2002; 169: 702–713.[Abstract/Free Full Text]

66. Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ, Vandivier RW, Wang N, Greenberg S, Dale BM, Qin C, Henson PM, Tall AR. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol. 2006; 174: 547–556.[Abstract/Free Full Text]

67. Patel VA, Longacre A, Hsiao K, Fan H, Meng F, Mitchell JE, Rauch J, Ucker DS, Levine JS. Apoptotic cells, at all stages of the death process, trigger characteristic signaling events that are divergent from and dominant over those triggered by necrotic cells: Implications for the delayed clearance model of autoimmunity. J Biol Chem. 2006; 281: 4663–4670.[Abstract/Free Full Text]

68. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005; 25: 2255–2264.[Abstract/Free Full Text]

69. Arai S, Shelton JM, Chen M, Bradley MN, Castrillo A, Bookout AL, Mak PA, Edwards PA, Mangelsdorf DJ, Tontonoz P, Miyazaki T. A role for the apoptosis inhibitory factor AIM/Spalpha/Api6 in atherosclerosis development. Cell Metab. 2005; 1: 201–213.[CrossRef][Medline] [Order article via Infotrieve]

70. Liu J, Thewke DP, Su YR, Linton MF, Fazio S, Sinensky MS. Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol. 2005; 25: 174–179.[Abstract/Free Full Text]

71. Johnson JL, Baker AH, Oka K, Chan L, Newby AC, Jackson CL, George SJ. Suppression of atherosclerotic plaque progression and instability by tissue inhibitor of metalloproteinase-2: involvement of macrophage migration and apoptosis. Circulation. 2006; 113: 2435–2444.[Abstract/Free Full Text]

72. Schrijvers DM, De Meyer GR, Kockx MM, Herman AG, Martinet W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25: 1256–1261.[Abstract/Free Full Text]

73. Boisvert WA, Rose DM, Boullier A, Quehenberger O, Sydlaske A, Johnson KA, Curtiss LK, Terkeltaub R. Leukocyte transglutaminase 2 expression limits atherosclerotic lesion size. Arterioscler Thromb Vasc Biol. 2006; 26: 563–569.[Abstract/Free Full Text]

74. Salvayre R, Auge N, Benoist H, Negre-Salvayre A. Oxidized low-density lipoprotein-induced apoptosis. Biochim Biophys Acta. 2002; 1585: 213–221.[Medline] [Order article via Infotrieve]

75. Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R, Tabas I. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol. 2005; 171: 61–73.[Abstract/Free Full Text]

76. Leppanen O, Bjornheden T, Evaldsson M, Boren J, Wiklund O, Levin M. ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo. Atherosclerosis. 2006; 188: 323–330.[CrossRef][Medline] [Order article via Infotrieve]

77. Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, Marks AR, Ron D, Tabas I. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 2003; 5: 781–792.[CrossRef][Medline] [Order article via Infotrieve]

78. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006; 86: 1133–1149.[Abstract/Free Full Text]

79. Zhou J, Werstuck GH, Lhotak S, de Koning AB, Sood SK, Hossain GS, Moller J, Ritskes-Hoitinga M, Falk E, Dayal S, Lentz SR, Austin RC. Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation. 2004; 110: 207–213.[Abstract/Free Full Text]

80. Feng B, Zhang D, Kuriakose G, Devlin CM, Kockx M, Tabas I. Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis. Proc Natl Acad Sci U S A. 2003; 100: 10423–10428.[Abstract/Free Full Text]

81. Li Y, Schwabe RF, DeVries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, Davis RJ, Flavell R, Brenner DA, Tabas I. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem. 2005; 280: 21763–21772.[Abstract/Free Full Text]

82. Hu P, Han Z, Couvillon AD, Exton JH. Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem. 2004; 279: 49420–49429.[Abstract/Free Full Text]

83. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997; 91: 231–241.[CrossRef][Medline] [Order article via Infotrieve]

84. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96: 857–868.[CrossRef][Medline] [Order article via Infotrieve]

85. Huang WC, Chen CC. Akt phosphorylation of p300 at Ser-1834 is essential for its histone acetyltransferase and transcriptional activity. Mol Cell Biol. 2005; 25: 6592–6602.[Abstract/Free Full Text]

86. Liu Y, Denlinger CE, Rundall BK, Smith PW, Jones DR. Suberoylanilide hydroxamic acid induces Akt-mediated phosphorylation of p300, which promotes acetylation and transcriptional activation of RelA/p65. J Biol Chem. 2006; 281: 31359–31368.[Abstract/Free Full Text]

87. Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A. Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci U S A. 2005; 102: 11278–11283.[Abstract/Free Full Text]

88. Mauro C, Crescenzi E, De Mattia R, Pacifico F, Mellone S, Salzano S, de Luca C, D’Adamio L, Palumbo G, Formisano S, Vito P, Leonardi A. Central role of the scaffold protein tumor necrosis factor receptor-associated factor 2 in regulating endoplasmic reticulum stress-induced apoptosis. J Biol Chem. 2006; 281: 2631–2638.[Abstract/Free Full Text]

89. Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999; 401: 86–90.[CrossRef][Medline] [Order article via Infotrieve]

90. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999; 401: 82–85.[CrossRef][Medline] [Order article via Infotrieve]

91. Song L, De Sarno P, Jope RS. Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. J Biol Chem. 2002; 277: 44701–44708.[Abstract/Free Full Text]

92. Ballif BA, Blenis J. Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ. 2001; 12: 397–408.[Free Full Text]

93. Ogata M, Hino SI, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K. Autophagy is activated for cell survival after ER stress. Mol Cell Biol. 2006;[Epub ahead of print].

94. Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem. 2006; 281: 30299–30304.[Abstract/Free Full Text]

95. Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol. 2006; 172: 719–731.[Abstract/Free Full Text]

96. Jia G, Cheng G, Gangahar DM, Agrawal DK. Insulin-like growth factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells. Immunol Cell Biol. 2006; 84: 448–454.[CrossRef][Medline] [Order article via Infotrieve]

97. Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P, Kroemer G. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005; 25: 1025–1040.[Abstract/Free Full Text]

98. Seimon TA, Obstfeld A, Moore KJ, Golenbock DT, Tabas I. Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc Natl Acad Sci U S A. 2006; 103: 19794–19799.[Abstract/Free Full Text]

99. Navarro A, Anand-Apte B, Tanabe Y, Feldman G, Larner AC. A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion. J Leukoc Biol. 2003; 73: 540–545.[Abstract/Free Full Text]

100. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112: 1796–1808.[CrossRef][Medline] [Order article via Infotrieve]

101. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112: 1821–1830.[CrossRef][Medline] [Order article via Infotrieve]

102. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996; 271: 665–668.[Abstract]

103. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997; 389: 610–614.[CrossRef][Medline] [Order article via Infotrieve]

104. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001; 293: 1673–1677.[Abstract/Free Full Text]

105. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med. 2005; 11: 191–198.[CrossRef][Medline] [Order article via Infotrieve]

106. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11: 183–190.[CrossRef][Medline] [Order article via Infotrieve]

107. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006; 116: 3015–3025.[CrossRef][Medline] [Order article via Infotrieve]

108. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y, Ogawa Y. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol. 2007; 27: 84–91.[Abstract/Free Full Text]

109. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature. 2002; 420: 333–336.[CrossRef][Medline] [Order article via Infotrieve]

110. Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, Luthringer D, Xu XP, Rajavashisth TB, Yano J, Kaul S, Arditi M. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001; 104: 3103–3108.[Abstract/Free Full Text]

111. Yang X, Coriolan D, Murthy V, Schultz K, Golenbock DT, Beasley D. Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling. Am J Physiol Heart Circ Physiol. 2005; 289: H1069–H1076.[Abstract/Free Full Text]

112. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity. 1999; 11: 115–122.[CrossRef][Medline] [Order article via Infotrieve]

113. Chan ED, Winston BW, Jarpe MB, Wynes MW, Riches DW. Preferential activation of the p46 isoform of JNK/SAPK in mouse macrophages by TNF alpha. Proc Natl Acad Sci U S A. 1997; 94: 13169–13174.[Abstract/Free Full Text]

114. Savage DB, Petersen KF, Shulman GI. Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension. 2005; 45: 828–833.[Abstract/Free Full Text]

115. Hodis HN, Mack WJ, Zheng L, Li Y, Torres M, Sevilla D, Stewart Y, Hollen B, Garcia K, Alaupovic P, Buchanan TA. Effect of peroxisome proliferator-activated receptor gamma agonist treatment on subclinical atherosclerosis in patients with insulin-requiring type 2 diabetes. Diabetes Care. 2006; 29: 1545–1553.[Abstract/Free Full Text]

116. Forst T, Hohberg C, Fuellert SD, Lubben G, Konrad T, Lobig M, Weber MM, Sachara C, Gottschall V, Pfutzner A. Pharmacological PPARgamma stimulation in contrast to beta cell stimulation results in an improvement in adiponectin and proinsulin intact levels and reduces intima media thickness in patients with type 2 diabetes. Horm Metab Res. 2005; 37: 521–527.[CrossRef][Medline] [Order article via Infotrieve]

117. Marfella R, D’Amico M, Esposito K, Baldi A, Di Filippo C, Siniscalchi M, Sasso FC, Portoghese M, Cirillo F, Cacciapuoti F, Carbonara O, Crescenzi B, Baldi F, Ceriello A, Nicoletti GF, D’Andrea F, Verza M, Coppola L, Rossi F, Giugliano D. The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: effects of rosiglitazone treatment. Diabetes. 2006; 55: 622–632.[Abstract/Free Full Text]

118. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006; 368: 1096–1105.[CrossRef][Medline] [Order article via Infotrieve]

119. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306: 457–461.[Abstract/Free Full Text]

120. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006; 313: 1137–1140.[Abstract/Free Full Text]

121. Funaoka M, Komatsu M, Toyoshima I, Mikami K, Ono T, Hoshino T, Kato J, Kuramitsu T, Ishii T, Masamune O. Tauroursodeoxycholic acid enhances phagocytosis of the cultured rat Kupffer cell. J Gastroenterol Hepatol. 1999; 14: 652–658.[CrossRef][Medline] [Order article via Infotrieve]

122. Bukovsky M, Mlynarcik D, Ondrackova V. Immunomodulatory activity of amphiphilic antimicrobials on mouse macrophages. Int J Immunopharmacol. 1996; 18: 423–426.[CrossRef][Medline] [Order article via Infotrieve]

123. Bonapace G, Waheed A, Shah GN, Sly WS. Chemical chaperones protect from effects of apoptosis-inducing mutation in carbonic anhydrase IV identified in retinitis pigmentosa 17. Proc Natl Acad Sci U S A. 2004; 101: 12300–12305.[Abstract/Free Full Text]

124. Ryu H, Smith K, Camelo SI, Carreras I, Lee J, Iglesias AH, Dangond F, Cormier KA, Cudkowicz ME, Brown RH Jr., Ferrante RJ. Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J Neurochem. 2005; 93: 1087–1098.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				J.-o Deguchi, H. Yamazaki, E. Aikawa, and M. Aikawa Chronic Hypoxia Activates the Akt and {beta}-Catenin Pathways in Human Macrophages Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1664 - 1670. [Abstract] [Full Text] [PDF]

				J. Oh, S. Weng, S. K. Felton, S. Bhandare, A. Riek, B. Butler, B. M. Proctor, M. Petty, Z. Chen, K. B. Schechtman, et al. 1,25(OH)2 Vitamin D Inhibits Foam Cell Formation and Suppresses Macrophage Cholesterol Uptake in Patients With Type 2 Diabetes Mellitus Circulation, August 25, 2009; 120(8): 687 - 698. [Abstract] [Full Text] [PDF]

				A. Sultan, D. Strodthoff, A.-K. Robertson, G. Paulsson-Berne, J. Fauconnier, P. Parini, M. Ryden, N. Thierry-Mieg, M. E. Johansson, A. V. Chibalin, et al. T Cell-Mediated Inflammation in Adipose Tissue Does Not Cause Insulin Resistance in Hyperlipidemic Mice Circ. Res., April 24, 2009; 104(8): 961 - 968. [Abstract] [Full Text] [PDF]

				H. Gonzalez-Navarro, A. Vinue, M. Vila-Caballer, A. Fortuno, O. Beloqui, G. Zalba, D. Burks, J. Diez, and V. Andres Molecular Mechanisms of Atherosclerosis in Metabolic Syndrome: Role of Reduced IRS2-Dependent Signaling Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2187 - 2194. [Abstract] [Full Text] [PDF]

				T. Senokuchi, C.-P. Liang, T. A. Seimon, S. Han, M. Matsumoto, A. S. Banks, J.-H. Paik, R. A. DePinho, D. Accili, I. Tabas, et al. Forkhead Transcription Factors (FoxOs) Promote Apoptosis of Insulin-Resistant Macrophages During Cholesterol-Induced Endoplasmic Reticulum Stress Diabetes, November 1, 2008; 57(11): 2967 - 2976. [Abstract] [Full Text] [PDF]

				D. C. Dale, L. Boxer, and W. C. Liles The phagocytes: neutrophils and monocytes Blood, August 15, 2008; 112(4): 935 - 945. [Abstract] [Full Text] [PDF]

				E. Herczenik and M. F. B. G. Gebbink Molecular and cellular aspects of protein misfolding and disease FASEB J, July 1, 2008; 22(7): 2115 - 2133. [Abstract] [Full Text] [PDF]

				M. Minami, K. Shimizu, Y. Okamoto, E. Folco, M.-L. Ilasaca, M. W. Feinberg, M. Aikawa, and P. Libby Prostaglandin E Receptor Type 4-associated Protein Interacts Directly with NF-{kappa}B1 and Attenuates Macrophage Activation J. Biol. Chem., April 11, 2008; 283(15): 9692 - 9703. [Abstract] [Full Text] [PDF]

				J. W. Han, K. Shimada, W. Ma-Krupa, T. L. Johnson, R. M. Nerem, J. J. Goronzy, and C. M. Weyand Vessel Wall-Embedded Dendritic Cells Induce T-Cell Autoreactivity and Initiate Vascular Inflammation Circ. Res., March 14, 2008; 102(5): 546 - 553. [Abstract] [Full Text] [PDF]

This Article Free upon publication Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liang, C.-P. Articles by Tall, A. R. Search for Related Content PubMed PubMed Citation Articles by Liang, C.-P. Articles by Tall, A. R.