doi: 10.1161/01.RES.0000259393.89870.58
© 2007 American Heart Association, Inc.
Editorials |
Fat Fuels the Flame
Triglyceride-Rich Lipoproteins and Arterial Inflammation
From the Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Peter Libby, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
See related article, pages 381–390
Key Words: very low density lipoprotein • endothelium • apolipoprotein CIII • atherosclerosis • coronary risk factors
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Introduction |
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 Top Introduction Does the Prevailing Model...Lipid Triggers for Atherogenesis...Proinflammatory Mechanisms of...Putting Proinflammatory...References |
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Recent reviews duly recite the prevailing concept of the mechanisms of atherogenesis.1–5 According to this model, a surfeit of low-density lipoproteins (LDL) favors accumulation and retention of these particles in the arterial intima. There, LDL undergoes oxidative modification. Lipid mediators derived from this oxidized LDL stoke the inflammation now widely deemed a critical culprit in the formation and complication of atheroma.6
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Does the Prevailing Model Explain Atherogenesis? |
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TopIntroductionDoes the Prevailing Model...Lipid Triggers for Atherogenesis...Proinflammatory Mechanisms of...Putting Proinflammatory...References |
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This oft repeated schema rests on a firm experimental foundation. Clinical and human pathological observations corroborate this view. Yet, the "oxidized LDL" hypothesis may not explain all aspects of atherogenesis. Most laboratory experiments with oxidized LDL use mixtures of products of incubation of LDL with transition metals. The Fenton chemistry used to generate oxidized LDL in the laboratory may have little to do with the oxidative processes at work in the atherosclerotic arterial wall. Biochemical studies have however begun to identify the structures of components oxidized LDL that do elicit proinflammatory effect on cells involved in atherogenesis.3,4 The lack of clinical benefit of antioxidant vitamin supplements does not alone vitiate a pathogenic role for oxidized LDL.7,8 Antioxidant vitamins may well not distribute to the proper compartments or may be chemically inappropriate agents for the oxidation chemistry that pertains to lipoproteins entwined with the intimal extracellular matrix during atherogenesis. The clinical trials of antioxidant vitamins may have enrolled patients at a stage of their disease too advanced to show a benefit of the antioxidant strategy.
LDL lowering does consistently confer clinical benefit, even in trials in which antioxidants have failed to do so. Yet the most aggressive LDL-lowering regimens still do not prevent the majority of events.9 For these reasons, we need to seek pathways beyond LDL that drive atherogenesis and its associated heightened inflammation.
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Lipid Triggers for Atherogenesis Beyond LDL |
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TopIntroductionDoes the Prevailing Model...Lipid Triggers for Atherogenesis...Proinflammatory Mechanisms of...Putting Proinflammatory...References |
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Manipulation of high-density lipoprotein (HDL) furnishes one attractive strategy. Numerous observational studies support strongly the inverse association of HDL and cardiovascular events. Strong experimental and human genetic studies have revealed molecular pathways by which HDL may protect against atherosclerosis by effecting reverse cholesterol transport or by antiinflammatory actions. Diet, physical activity, and some classes of pharmacological agents can raise HDL levels, but we still lack clinical evidence that therapeutic elevation of HDL confers clinical benefit. The recent finding reported in the lay press of excess mortality with one cholesteryl ester transfer protein inhibitor that handsomely boosted HDL level could relate to an idiosyncratic effect of that particular molecule or to inefficacy of this approach to HDL elevation. Conclusions in this regard must await at least the analysis and publication of the clinical end point and imaging trials with this agent.
Levels of HDL usually vary inversely with triglyceride concentration. Epidemiologists still fret over whether triglycerides actually comprise a risk factor for cardiovascular events independent of HDL or of glycemic control in diabetic individuals. Triglyceride levels depend exquisitely on diet and vary from hour to hour, challenging such analysis in large populations, and rendering HDL the more reliably measured of the twain. Partly for this reason, the notion of postprandial lipemia as an atherogenic risk factor, championed by Zilversmit, remains incompletely explored.10 Turning the usual notion on its head, could the traditional dependent variable in such analyses (triglyceride levels) become the independent variable? Could triglyceride-rich lipoproteins directly promote atherogenesis and trigger inflammation? Should triglyceride-rich lipoproteins become a target for intervention?
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Proinflammatory Mechanisms of Triglyceride-Rich Lipoproteins? |
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TopIntroductionDoes the Prevailing Model...Lipid Triggers for Atherogenesis...Proinflammatory Mechanisms of...Putting Proinflammatory...References |
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Dwarfed by the voluminous data regarding proinflammatory effects of LDL and its derivatives, we possess scant information about triglycerides or triglyceride-rich lipoproteins as instigators of inflammation and other atherogenic functions of cells found in plaques. In 1999, Dichtl and colleagues reported that the triglyceride-rich lipoprotein very low-density lipoprotein (VLDL) activates the pivotal transcriptional regulator of inflammation nuclear factor-kappa B (NF-
B).11 As lipoproteins can bind bacterial lipopolysaccharides, ubiquitous laboratory contaminants that can activate inflammatory signaling in vascular cells and leukocytes in minute concentrations, such results bear careful scrutiny and replication. In this issue of Circulation Research Ting et al provide further independent data that support a role for triglyceride-rich lipoproteins in inflammatory activation of vascular cells in vitro.12 They found that triglyceride-rich lipoproteins at postprandial concentrations do not alone elicit an inflammatory response in human aortic endothelial cells. Treatment of the endothelial cells with the triglyceride-rich lipoproteins did substantially raise the expression of leukocyte adhesion molecules and monocyte adherence in response to the proinflammatory cytokine tumor necrosis factor-
(TNF-). Lipopolysaccharide levels measured in the lipoprotein preparations appeared low. The mechanism of this effect appeared to depend on LDL-receptor related proteins (LRP) and downstream activation of p38 MAP kinase and NF-B (Figure). The disparity between the Dichtl study that showed direct effects of VLDL on NF-B activation and the Ting study that demonstrated a potentiation of cytokines but no direct effect of triglyceride-rich lipoproteins alone on inflammatory functions of endothelial cells, will require further study. The specter of endotoxin contamination demands eternal vigilance in such quests. Interestingly, Stollenwerk et al showed that in human monocyte-derived macrophages VLDL potentiated lipopolysaccharide-induced TNF- expression but by itself did not do so.13 Another pro-inflammatory mechanism of triglyceride-rich lipoproteins could depend on their content of apolipoprotein CIII. Our recent work has shown that apolipoprotein CIII or VLDL that bear this apolipoprotein can increase monocytoid cell adhesion to endothelial cells in a vascular cell adhesion molecule-1–dependent manner.14,15 Apolipoprotein CIII appears to activate NF-B through a pertussis-sensitive G protein-protein kinase C–dependent pathway.16 Thus, triglyceride-rich lipoproteins can fan the flame of inflammation during atherogenesis in several ways (Figure).
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Putting Proinflammatory Mechanisms of Triglyceride-Rich Lipoproteins in Clinical Context |
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TopIntroductionDoes the Prevailing Model...Lipid Triggers for Atherogenesis...Proinflammatory Mechanisms of...Putting Proinflammatory...References |
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The risk factor profile of the typical patient with atherosclerosis is shifting at the advent of the 21st century. Our armementarium includes effective and clinically proven interventions to address high levels of LDL, the cardiovascular scourge of the latter half of the 20th century. We now face a burden of obesity and diabetes, and the attendant dyslipidemia noteworthy for elevated triglyceride-rich lipoproteins and low HDL rather than excessive LDL levels. Thus, the pressing current clinical cardiovascular challenges include mastery of triglyceride-rich lipoproteins. The emerging data regarding pathways that link features of dyslipidemia to inflammation and atherogenesis provide new insight into the mechanisms that underlie a burgeoning epidemic of heightened atherosclerotic risk because of dyslipidemia.
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Acknowledgments |
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Sources of Funding
This work is supported by the Donald W. Reynolds Foundation and the National Heart, Lung, and Blood Institute.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association
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References |
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TopIntroductionDoes the Prevailing Model...Lipid Triggers for Atherogenesis...Proinflammatory Mechanisms of...Putting Proinflammatory...References |
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1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
2. Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell. 2001; 104: 503–516.[CrossRef][Medline] [Order article via Infotrieve]
3. Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Fonarow GC, Vahabzadeh K, Hama S, Hough G, Kamranpour N, Berliner JA, Lusis AJ, Fogelman AM. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res. 2004; 45: 993–1007.
4. Berliner JA, Watson AD. A role for oxidized phospholipids in atherosclerosis. N Engl J Med. 2005; 353: 9–11.
5. Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical practice. J Am Coll Cardiol. 2006; 48: A33–A46.
6. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6: 508–519.[CrossRef][Medline] [Order article via Infotrieve]
7. Kris-Etherton PM, Lichtenstein AH, Howard BV, Steinberg D, Witztum JL. Antioxidant vitamin supplements and cardiovascular disease. Circulation. 2004; 110: 637–641.
8. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J, Jr. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354: 1567–1577.
9. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005; 46: 1225–1228.
10. Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem. 1995; 41: 153–158.
11. Dichtl W, Nilsson L, Goncalves I, Ares MP, Banfi C, Calara F, Hamsten A, Eriksson P, Nilsson J. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res. 1999; 84: 1085–1094.
12. Ting HJ, Stice JP, Schaff UY, Hui DY, Rutledge JC, Knowlton AA, Passerini AG, Simon SI. Triglyceride-rich lipoproteins prime aortic endothelium for inflammatory responses to TNF-. Circ Res. 2007; 100: 381–390.
13. Stollenwerk MM, Schiopu A, Fredrikson GN, Dichtl W, Nilsson J, Ares MP. Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages. Atherosclerosis. 2005; 179: 247–254.[CrossRef][Medline] [Order article via Infotrieve]
14. Kawakami A, Aikawa M, Libby P, Alcaide P, Luscinskas FW, Sacks FM. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation. 2006; 113: 691–700.
15. Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby P, Sacks FM. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation. 2006; 114: 681–687.
16. Kawakami A, Aikawa M, Nitta N, Yoshida M, Libby P, Sacks FM. ApolipoproteinCIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G-protein- and protein kinase Ca-mediated nuclear factor-kB activation. Arterioscler Thromb Vasc Biol. 2007; 27: 219–225.
Related Article:
Circ. Res. 2007 100: 381-390.
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