© 2000 American Heart Association, Inc.
Clinical Research |
Myocardial Cell Death in Human Diabetes
From the Department of Medicine (J.K., I.J., A.L., B.N.-G., P.A.), New York Medical College, Valhalla, NY, and Department of Cardiology (A.F., C.C., A.M.), Sacred Heart University, Rome, Italy.
Correspondence to Piero Anversa, MD, Department of Medicine, New York Medical College, Vosburgh Pavilion, Room 302, Valhalla, NY 10595. E-mail piero_anversa{at}nymc.edu
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Abstract |
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Abstract—The renin-angiotensin system is upregulated with diabetes, and this may contribute to the development of a dilated myopathy. Angiotensin II (Ang II) locally may lead to oxidative damage, activating cardiac cell death. Moreover, diabetes and hypertension could synergistically impair myocardial structure and function. Therefore, apoptosis and necrosis were measured in ventricular myocardial biopsies obtained from diabetic and diabetic-hypertensive patients. Accumulation of a marker of oxidative stress, nitrotyrosine, and Ang II labeling were evaluated quantitatively. The diabetic heart showed cardiac hypertrophy, cavitary dilation, and depressed ventricular performance. These alterations were more severe with diabetes and hypertension. Diabetes was characterized by an 85-fold, 61-fold, and 26-fold increase in apoptosis of myocytes, endothelial cells, and fibroblasts, respectively. Apoptosis in cardiac cells did not increase additionally with diabetes and hypertension. Diabetes increased necrosis by 4-fold in myocytes, 9-fold in endothelial cells, and 6-fold in fibroblasts. However, diabetes and hypertension increased necrosis by 7-fold in myocytes and 18-fold in endothelial cells. Similarly, Ang II labeling in myocytes and endothelial cells increased more with diabetes and hypertension than with diabetes alone. Nitrotyrosine localization in cardiac cells followed a comparable pattern. In spite of the difference in the number of nitrotyrosine-positive cells with diabetes and with diabetes and hypertension, apoptosis and necrosis of myocytes, endothelial cells, and fibroblasts were detected only in cells containing this modified amino acid. In conclusion, local increases in Ang II with diabetes and with diabetes and hypertension may enhance oxidative damage, activating cardiac cell apoptosis and necrosis.
Key Words: oxidative damage • renin-angiotensin system • nitrotyrosine • heart failure
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Introduction |
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Non–insulin-dependent diabetes mellitus (NIDDM) is characterized by the development of a cardiac myopathy that deteriorates with time.1 This myopathy often manifests itself with diastolic dysfunction, but whether in the absence of coronary artery disease and hypertension, severe ventricular decompensation occurs, remains controversial. Biochemical and mechanical abnormalities of the myocardium have been identified with diabetes.2 3 4 However, cardiac hypertrophy shows essentially identical alterations,5 raising the possibility that diabetes may initially induce a hypertrophic myopathy, which evolves chronically into a dilated form with markedly depressed contractile behavior. Recent observations point to an upregulation of the local renin-angiotensin system (RAS) and the synthesis of angiotensin II (Ang II) as critical factors in the activation of myocyte apoptosis and reactive hypertrophy in a model of insulin-dependent diabetes.6 Severe hypertension involves stimulation of the systemic and local RAS,7 8 myocyte loss, and cellular hypertrophy,9 suggesting that diabetes and hypertension together may synergistically damage the structure and function of the overloaded human heart.
A direct correlation exists between hyperglycemia and oxidative stress.10 11 Ang II stimulates the production of reactive O2,12 13 14 and the detrimental effects of Ang II with diabetes have been shown clinically15 and experimentally.6 Thus, Ang II and oxidative damage may be critical in the onset of a diabetic myopathy. Hypertension may enhance Ang II formation, potentiating the cardiac damage in NIDDM. To address these issues, cell death by apoptosis and necrosis was evaluated in myocardial biopsies obtained from patients with NIDDM alone and in combination with hypertension. Cell death was quantitated separately in myocytes, endothelial cells, and fibroblasts to establish the effects of these diseases on the different cardiac cell populations. Additionally, Ang II labeling and the localization of nitrotyrosine in myocytes, endothelial cells, and fibroblasts were measured quantitatively. Nitrotyrosine was determined, because this modified amino acid is a product of reactive O2.16
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Materials and Methods |
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Patients
Sixteen men and 7 women with diabetes (11 patients; 57±10 years of age) or diabetes and hypertension (12 patients; 58±13 years of age) and New York Heart Association (NYHA) class II through IV were studied. Echocardiography, cardiac catheterization, and coronary angiography were performed, and left ventricular (LV) endomyocardial biopsies were obtained. Measurements included LV end-systolic (LVESD) and end-diastolic (LVEDD) diameters, septal (LVST) and posterior (LVPT) LV wall thickness, wall thickness-to-chamber radius ratio (LVPT/CR), ejection fraction (EF), fractional shortening (FS), and LV mass (LVM).17 The study was approved by the institutional review committee, and patients gave informed consent. Ten nondiseased hearts collected at autopsy were used for control morphometric measurements.18 Autopsy hearts processed several hours after death do not allow estimation of cell necrosis.19 Baseline cell death was assessed in 10 surgical specimens of papillary muscles from patients with mitral stenosis. This analysis was complemented by cell-death determinations in LV myocardial samples obtained from five additional subjects who died from causes other than cardiovascular diseases and underwent autopsy within 3 to 9 hours after death.19
Myocardial Sampling
In all patients, 2 to 3 endomyocardial biopsies,
approximately 3 mm3 each, were collected
from the LV and embedded in paraffin. Samples from the LV
endomyocardium of 15 autopsy hearts and 10 specimens of papillary
muscles were similarly treated. Ang II localization was measured in
frozen sections of 1 to 2 biopsies from 8 of the 11 diabetic patients,
5 of the 12 diabetic-hypertensive patients, and 5 of the 10 papillary
muscles.
Volume Composition and Myocyte
Area
Volume fractions of myocytes and collagen and myocyte
cross-sectional area were obtained by confocal microscopy in sections
with transversely cut myocytes stained with 
-sarcomeric actin,
laminin, and collagen types I and
III.6 18
Cell Death and Nitrotyrosine
Terminal deoxynucleotidyl transferase (TdT) and in
situ ligation of hairpin probes with single-base 3' overhangs or blunt
ends were
used.6 19 20
Apoptosis was also measured by activated caspase-3 antibody and
apoptosis-necrosis by TdT and hairpin with blunt ends. Myocytes,
endothelial cells, and fibroblasts were detected by -sarcomeric
actin, factor VIII, and vimentin. Nitrotyrosine was identified by
nitrotyrosine antibody. Sections treated with 10% peroxynitrite and
degraded peroxynitrite were used as positive and negative controls,
respectively.
Angiotensin II
Frozen sections were incubated with Ang II antiserum
and with FITC-labeled goat anti-rabbit IgG. Specificity was determined
by preabsorption of 10 µL of antibody with 0.05 mg of antigen.
Nonimmune rabbit serum was also used as negative control. The number of
Ang II–positive sites per mm2 of myocytes
and endothelial cells was evaluated
quantitatively.21 Positive
control consisted of myocardium from diabetic rats; Ang II
concentration measured by ELISA in myocytes isolated from these hearts
was increased
14-fold.6
Statistics
Results are mean±SD. Significance between two values
was determined by Student’s t
test and among groups by Bonferroni’s method;
P<0.05 was considered
significant.
An expanded Materials and Methods section can be found in an online data supplement available at http://www.circresaha.org.
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Results |
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Patients
The duration of diabetes (D) varied from 3 to 12 years, averaging 6 years. Diabetes in hypertensive patients (DH) ranged from 3 to 17 years, with a mean of 12 years. Hypertension lasted 2 to 15 years, with an average of 9 years. Hypertension was a secondary event in 11 of the 12 patients and followed the onset of diabetes by 1 to 8 years. In one patient, hypertension preceded diabetes by one year. In the D group, 4 patients were in NYHA class II, 2 in class III, and 5 in class IV. In the DH group, 2 patients were in class III and 10 in class IV. Blood glucose levels were comparable in the 2 groups: D=190±39 mg/dL; DH=210±27 mg/dL. Treatment of D consisted of oral hypoglycemic drugs and angiotensin-converting enzyme (ACE) inhibitors. Patients with DH received also diuretics and ß-blockers. Four D and 8 DH patients were treated with digitalis.
Cardiac Performance
Functional parameters were abnormal in D and DH
patients: LVPT (D=9.8±1.7; DH=9.1±1.8 mm), LVST (D=10.2±1.7;
DH=10.9±1.5 mm), LVEDD (D=65±5; DH=72±7 mm), LVESD (D=50±6;
DH=58±6 mm), LVPT/CR (D=0.16±0.02; DH=0.13±0.03 mm/mm), LVM
(D=289±62; DH=360±74 g), FS (D=22±5; DH=19±4%), and EF (D=32±9;
DH=23±7%). In comparison with diabetes, LVEDD, LVESD, and LVM were
11% (P<0.02), 16%
(P<0.005), and 25%
(P<0.002) larger with diabetes
and hypertension. Moreover, LVPT/CR and EF decreased 23%
(P<0.04) and 28%
(P<0.02) more when
hypertension was present. Coronary angiography was normal in all 23
patients. This was the essential criterion for inclusion in the study.
Patients were not considered for cardiac transplantation at the time of
biopsy.
Scarring and Myocyte Hypertrophy
With respect to controls (4.4±1.5%), interstitial
fibrosis increased 18% (5.2±2%; NS) and 66% (7.3±2.2%;
P<0.01) in D and DH hearts,
respectively. Corresponding increases in replacement fibrosis were 42%
(control=5.5±1.8; D=7.8±2.8%, NS) and 134% (DH=12.9±3.6%,
P<0.001). Collagen
accumulation was 55% (P<0.05)
greater with DH than with D. Myocyte compartment decreased 7%
(P<0.001) with D and 14%
(P<0.001) with DH (not shown).
Transverse myocyte area
(Figure 1
) was 285±39, 394±76, and 519±101
µm2 in control, D, and DH hearts,
respectively. Myocytes hypertrophied 38%
(P<0.02) with D and 82%
(P<0.001) with DH. With DH,
myocytes were 32% (P<0.005)
larger than with diabetes.
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Cell Death
Apoptosis was measured by TdT assay, in situ ligation
with a hairpin probe, and activated caspase-3 in combination with TdT.
TdT identifies double-strand DNA cleavage with 1- to 4-base 3'
overhangs. The hairpin probe recognizes internucleosomal DNA cleavage
with single-base 3' overhang
only.19 20 Cell
necrosis was assessed with a hairpin probe detecting double-strand DNA
cleavage with blunt ends.19
Activated caspase-3 is linked to the stimulation of endonucleases and,
thereby, DNA
fragmentation.22 Apoptosis
and necrosis of myocytes, endothelial cells, and fibroblasts are
illustrated in
Figures 2 and 3. The concurrent localization of
TdT and activated caspase-3 in apoptotic cells is shown in
Figures 2J through 2L. The analysis of 20 myocytes, 19
endothelial cells, and 11 fibroblasts from D hearts and 16 myocytes, 15
endothelial cells, and 10 fibroblasts from DH hearts demonstrated that
all cells examined were TdT-positive and caspase-3–positive. Thus,
labeling of nuclei by caspase-3 confirmed the results obtained by the
detection of DNA strand breaks in cardiac cells with TdT or hairpin
probe. Additionally, death by apoptosis was never found in combination
with necrosis in the same cell.
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Control values for apoptosis and necrosis in LV myocardium
(C1, n=5) and papillary muscles
(C2, n=10) are illustrated separately in
Figures 4A through 4C. These baseline measurements were not
statistically different. Therefore, they were averaged for comparisons
with the diseased hearts. Diabetes was characterized by an 85-, 61-,
and 26-fold increase in apoptosis of myocytes, endothelial cells, and
fibroblasts, respectively. Diabetes and hypertension did not increase
additionally the level of apoptosis in cardiac cells. Values of myocyte
and endothelial cell apoptosis were similar with D and DH but were
significantly higher than fibroblast apoptosis in both cases. There was
no difference between apoptosis measured by TdT or hairpin probe
(Figures 4A and 4B). Diabetes increased necrosis by 4-fold in
myocytes, 9-fold in endothelial cells, and 6-fold in fibroblasts
(Figure 4C). However, diabetes and hypertension increased
this form of cell death by 7-fold in myocytes, 18-fold in endothelial
cells, and 6-fold in fibroblasts. Myocyte and endothelial cell necrosis
with DH were 2-fold higher than with D alone.
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P<0.05 vs value of myocytes
in D and DH.
Angiotensin II
Myocardial samples, frozen immediately after
dissection, were used for the immunocytochemical localization of Ang II
in myocytes and endothelial cells
(Figures 5A through 5H). Myocytes were stained by
-sarcomeric actin, and the interstitium was labeled by laminin to
outline cell profiles. Endothelial cells were identified by factor VIII
only; laminin obscured the detection of Ang II in these small cells.
Myocardium from diabetic rats was used as a positive control for Ang II
localization.6 As expected, a
several-fold higher level of labeling was found in the animal model
(Figures 5I and 5J). Preabsorption of the primary antibody
with Ang II resulted in the lack of labeling in human samples (not
shown) and rat diabetic left ventricle
(Figures 5K and 5L). Diabetes in humans increased 3.4- and
3.1-fold Ang II labeling of myocytes and endothelial cells,
respectively
(Figure 5M). Diabetes and hypertension together increased
additionally 
2-fold Ang II localization in these cell types. The
density of Ang II sites per unit area of cell was 5- to 6-fold higher
in endothelial cells than myocytes in all
conditions.
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Nitrotyrosine
Nitrotyrosine localization is shown in
Figures 6A through 6F. In control muscles, the fraction of
nitrotyrosine-positive cells was higher in myocytes than endothelial
cells and fibroblasts. Diabetes doubled the percentages of myocytes and
endothelial cells with nitrotyrosine; the frequency of labeled
fibroblasts did not vary. To validate the cytochemical assay, control
LV human myocardium was exposed to peroxynitrite before nitrotyrosine
staining. Conversely, similar tissue sections were treated with
degraded peroxynitrite before nitrotyrosine labeling. As expected, the
first procedure resulted in a complete nitrotyrosine staining of the
myocardium, whereas the second protocol left the tissue minimally
labeled
(Figures 6G through 6J). With diabetes and hypertension, 91%
myocytes and 25% endothelial cells contained nitrotyrosine
(Figure 6K). A possible link between oxidative stress and
cell death was determined
(Figure 7) by evaluating 17 and 23 apoptotic myocytes and 15
and 14 apoptotic endothelial cells with D and DH, respectively. In all
cases, apoptosis was accompanied by nitrotyrosine. Because of the high
percentage of nitrotyrosine-positive myocytes in these hearts, the
combination of nitrotyrosine and apoptosis was examined in control
muscles; again, apoptosis was detected only in myocytes with
nitrotyrosine (n=11). An identical association was established for
myocyte (D, n=33; DH, n=65) and endothelial cell (D, n=15; DH, n=32)
necrosis. Nitrotyrosine and DNA damage typical of necrosis was found in
all cells. Finally, apoptotic (D, n=13; DH, n=10) and necrotic (D,
n=14; DH, n=17) fibroblast death and the presence of nitrotyrosine were
measured. This was done because the fraction of nitrotyrosine-positive
fibroblasts did not increase with D or DH whereas the number of dying
fibroblasts increased. All dying fibroblasts showed
nitrotyrosine.
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Discussion |
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Diabetes, Diabetes and Hypertension, and Heart Failure
NIDDM led to myopathy in the absence of coronary artery disease and hypertension. Diabetes resulted in increased muscle mass, cavitary dilation, mural thinning, and depressed ventricular performance. These anatomical and functional characteristics reflect decompensated eccentric hypertrophy,23 a condition that was more severe when diabetes and hypertension were present. However, diabetes produced these effects in half the period of diabetes and hypertension. This difference suggests that diabetes was better controlled in diabetic-hypertensive patients or that hypertension counteracted initially the consequences of diabetes on cardiac restructuring. Hypertension promotes an increase in wall thickness,23 and early in the course of the disease, this hypertrophic response may have attenuated the expansion in chamber volume and diastolic dysfunction with diabetes.15 This form of adaptation has been shown experimentally shortly after coronary artery constriction and renal hypertension.24 Whether this type of apparent compensation actually occurs in humans is difficult to envision.
Complex is understanding how diabetes per se affects ventricular remodeling. At its onset, NIDDM results in myocardial hypertrophy and impaired cardiac function in spite of greater mass and thickened wall in humans.25 This suggests that defects in muscle mechanical behavior are operative in diabetes. The depression in contractility occurs before the myopathy progresses to the phase analyzed here, in which myocardial scarring and ongoing cell death contributed to ventricular dilation, wall thinning, and depressed hemodynamics. The hypertensive9 26 and diabetic-hypertensive heart evolve in a similar manner. Myocyte death is a shared pathological event that occurs chronically in the diseased heart,19 27 but its actual role in the transition from compensated to decompensated hypertrophy and failure remains controversial.28 Cell death is required for acute expansion in cavitary volume, and myocyte death and growth are critical determinants of cardiac remodeling of ischemic and nonischemic origin.29
Diabetes, Diabetes and Hypertension,
and Cell Death
Apoptosis and necrosis were detected in myocytes,
endothelial cells, and fibroblasts of the failing diabetic and
diabetic-hypertensive heart. Myocyte and endothelial cell apoptosis
varied from 0.06% to 0.07% in the 2 groups of patients, whereas
myocyte and endothelial cell necrosis ranged from 0.07% to 0.1% with
diabetes and from 0.15% to 0.18% with diabetes and hypertension.
Apoptosis and necrosis involved lower fractions of fibroblasts. Cardiac
cell apoptosis did not differ in patients with diabetes and with
diabetes and hypertension. Conversely, necrosis of myocytes and
endothelial cells was significantly higher with diabetes and
hypertension than with diabetes alone. Necrosis of myocytes and
endothelial cells was 1.4- and 2.5-fold higher than apoptosis with
diabetes and diabetes and hypertension, respectively.
Myocyte death has previously been measured in end-stage cardiac failure by the methods used here.19 However, in the terminal phases of cardiac decompensation, the values for apoptotic and necrotic myocytes were 3- and 7-fold higher, respectively. Moreover, the more compromised diabetic-hypertensive heart had a larger fraction of dying myocytes. These findings strengthen the notion that the extent of ongoing myocyte death parallels the severity of the disease and its stage of evolution. Endothelial cell death may have comparable implications. Myocytes and capillary endothelial cells, which are functionally interdependent and have a one-to-one ratio,30 are similarly affected by apoptosis and necrosis in the failing human heart. Capillary density decreases in the hypertrophied heart in humans,31 and endothelial cell death with loss of capillary units may be relevant to the progression of cardiac decompensation. Reduction in capillary number results in a decrease in capillary surface available for oxygen diffusion and transport and an increase in the diffusion distance for oxygen.31 Alterations in the capillary properties controlling tissue oxygen distribution and consumption may lead to local ischemia and additional activation of cell-death mechanisms.
The identification of myocyte apoptosis in the heart in vivo has been challenged by electron microscopic analysis of tissue sections.28 As used, electron microscopy does not permit adequate sampling and the results are uninterpretable.32 The claim has also been made that molecular probes capable of identifying specific forms of DNA damage may result in an overestimation of apoptosis.33 This conclusion was reached on the theoretical basis that probes may recognize cell death when only 10% of the double DNA strand breaks required for apoptosis are detected. This argument is weak; one unrepaired double-strand cleavage is sufficient to kill a cell. As emphasized previously, evaluation of apoptosis by 3 independent histochemical methods and confocal microscopy provides an accurate assessment of this form of cell death.32
Diabetes, Diabetes and Hypertension,
and Ang II
The localization of Ang II increased in myocytes and
capillary endothelial cells of diabetic and diabetic-hypertensive
hearts. Ang II sites in these cells were 2-fold higher with diabetes
and hypertension than with diabetes alone. Ang II labeling in
endothelial cells was 5- to 6-fold greater than in myocytes.
Stimulation of the cellular RAS occurred in spite of the fact that all
patients were treated with ACE inhibitors. Diabetes and diabetes and
hypertension activated the local RAS, and ACE inhibitors, directly or
indirectly, blocked only in part the generation of Ang II at the
cellular level. This is consistent with the limited capacity of ACE
inhibitors to traverse the plasma membrane and abolish the cytoplasmic
synthesis of Ang II.34
However, it cannot be excluded that enhanced Ang II labeling reflected
increased binding to endogenous receptors.
Clinical15 and experimental6 results indicate that diabetes is characterized by upregulation of the systemic and local RAS, and interventions attenuating the effects of Ang II positively interfere with morbidity, mortality, and the development of a diabetic myopathy. Ang II triggers cell death35 and promotes cell growth,36 which are present with diabetes and diabetes and hypertension. The difference in Ang II labeling between the diabetic and the diabetic-hypertensive heart is consistent with the difference in cardiac mass, myocyte cross-sectional area, replacement fibrosis, cell death, and ventricular performance found in these 2 groups of patients. Enhanced generation of Ang II in the myocardium may explain the increase in mural thickness and mass detected in diabetic Native Americans.25 The mechanism activating the local RAS has not been identified. Angiotensinogen (Aogen) is the limiting factor in the synthesis of Ang II,37 and p53 promotes transcription of Aogen and AT1, enhancing Ang II formation and Ang II–mediated responses in myocytes.35 37 These effects are blocked by losartan. Hyperglycemia may result in p53 glycosylation and expression of Aogen and AT1 receptor.6 On this basis, AT1 blockade might be more beneficial than ACE inhibition in counteracting the impact of Ang II on cell growth and cell death with diabetes.
Diabetes, Diabetes and Hypertension,
and Oxidative Stress
Nitric oxide (NO) can interact with superoxide-forming
peroxynitrite. Peroxynitrite may decompose into oxidants with
reactivity similar to hydroxyl radical–forming
nitrotyrosine.16
Nitrotyrosine may also derive from inflammatory cells and the
interaction between myeloperoxidase and nitrogen dioxide, independently
from NO.38 Cell necrosis is
associated with an inflammatory response surrounding the dying cell,
but this phenomenon is apparent after DNA fragmentation has
occurred.19 Whether the
accumulation of nitrotyrosine with diabetes and diabetes and
hypertension was mediated by NO or other enzymatic pathways cannot be
ascertained at present. However, with diabetes, nitrotyrosine increased
in all cardiac cells and, with diabetes and hypertension, increased
additionally in myocytes and endothelial cells. The percentage of
myocytes expressing nitrotyrosine was much higher than endothelial
cells and fibroblasts. In spite of the difference in nitrotyrosine,
apoptosis and necrosis of myocytes, endothelial cells, and fibroblasts
were detected exclusively in cells containing this modified amino acid.
Thus, an association exists between oxidative stress and cell death
with diabetes and diabetes and hypertension. However, the present
observations do not allow to establish a cause-and-effect relationship
between these cellular events.
Studies in patients10 and animals11 have demonstrated a direct correlation between hyperglycemia and the production of reactive O2. Moreover, Ang II leads to an oxidative stress response through stimulation of NADH/NADPH oxidase.12 13 14 This enzyme is the major source of superoxide via the transfer of electrons from NADH or NADPH to O2.12 Such effects of Ang II are mediated through the AT1 receptor.14 On this basis, the possibility may be advanced that local increases in Ang II with diabetes and with diabetes and hypertension enhance oxidative damage, activating the death pathways implicated in cell apoptosis and necrosis. Different levels of reactive O2 condition distinct forms of cell death: high amounts induce necrosis and low quantities trigger apoptosis.39
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-38132, HL-39902, HL-43023, AG-15756, HL-65577, HL-66923, and AG-17042 and by grant JDFI 1-2000-62.
Received August 15, 2000; revision received October 27, 2000; accepted October 27, 2000.
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Y. Pang, P. Bounelis, J. C. Chatham, and R. B. Marchase Hexosamine Pathway Is Responsible for Inhibition by Diabetes of Phenylephrine-Induced Inotropy Diabetes, April 1, 2004; 53(4): 1074 - 1081. [Abstract] [Full Text] [PDF]
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D. Torella, M. Rota, D. Nurzynska, E. Musso, A. Monsen, I. Shiraishi, E. Zias, K. Walsh, A. Rosenzweig, M. A. Sussman, et al. Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression Circ. Res., March 5, 2004; 94(4): 514 - 524. [Abstract] [Full Text] [PDF]
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Y. Shimoni, M. Chuang, E. D. Abel, and David. L. Severson Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice J. Physiol., March 1, 2004; 555(2): 345 - 354. [Abstract] [Full Text] [PDF]
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R. Marfella, C. Di Filippo, K. Esposito, F. Nappo, E. Piegari, S. Cuzzocrea, L. Berrino, F. Rossi, D. Giugliano, and M. D'Amico Absence of Inducible Nitric Oxide Synthase Reduces Myocardial Damage During Ischemia Reperfusion in Streptozotocin-Induced Hyperglycemic Mice Diabetes, February 1, 2004; 53(2): 454 - 462. [Abstract] [Full Text]
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Y. Chandrashekhar, S. Sen, R. Anway, A. Shuros, and I. Anand Long-Term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction J. Am. Coll. Cardiol., January 21, 2004; 43(2): 295 - 301. [Abstract] [Full Text] [PDF]
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L. Quagliaro, L. Piconi, R. Assaloni, L. Martinelli, E. Motz, and A. Ceriello Intermittent High Glucose Enhances Apoptosis Related to Oxidative Stress in Human Umbilical Vein Endothelial Cells: The Role of Protein Kinase C and NAD(P)H-Oxidase Activation Diabetes, November 1, 2003; 52(11): 2795 - 2804. [Abstract] [Full Text] [PDF]
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C.-H. Huang, S. F. Vatner, A. P. Peppas, G. Yang, and R. K. Kudej Cardiac Nerves Affect Myocardial Stunning Through Reactive Oxygen and Nitric Oxide Mechanisms Circ. Res., October 31, 2003; 93(9): 866 - 873. [Abstract] [Full Text] [PDF]
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 T Hayashi, K Sohmiya, A Ukimura, S Endoh, T Mori, H Shimomura, M Okabe, F Terasaki, and Y Kitaura Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart Heart, October 1, 2003; 89(10): 1236 - 1242. [Abstract] [Full Text] [PDF]
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C. Cheng and D. W. Zochodne Sensory Neurons With Activated Caspase-3 Survive Long-Term Experimental Diabetes Diabetes, September 1, 2003; 52(9): 2363 - 2371. [Abstract] [Full Text] [PDF]
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A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF]
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E. Picano Diabetic cardiomyopathy: the importance of being earliest J. Am. Coll. Cardiol., August 6, 2003; 42(3): 454 - 457. [Full Text] [PDF]
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 A. Ceriello New Insights on Oxidative Stress and Diabetic Complications May Lead to a "Causal" Antioxidant Therapy Diabetes Care, May 1, 2003; 26(5): 1589 - 1596. [Abstract] [Full Text] [PDF]
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M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF]
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A. S. Neitzel, A. N. Carley, and D. L. Severson Chylomicron and palmitate metabolism by perfused hearts from diabetic mice Am J Physiol Endocrinol Metab, February 1, 2003; 284(2): E357 - E365. [Abstract] [Full Text] [PDF]
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 I. V. Turko and F. Murad Protein Nitration in Cardiovascular Diseases Pharmacol. Rev., December 1, 2002; 54(4): 619 - 634. [Abstract] [Full Text] [PDF]
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Y. Pang, D. L. Hunton, P. Bounelis, and R. B. Marchase Hyperglycemia Inhibits Capacitative Calcium Entry and Hypertrophy in Neonatal Cardiomyocytes Diabetes, December 1, 2002; 51(12): 3461 - 3467. [Abstract] [Full Text] [PDF]
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C. Szabo, A. Zanchi, K. Komjati, P. Pacher, A. S. Krolewski, W. C. Quist, F. W. LoGerfo, E. S. Horton, and A. Veves Poly(ADP-Ribose) Polymerase Is Activated in Subjects at Risk of Developing Type 2 Diabetes and Is Associated With Impaired Vascular Reactivity Circulation, November 19, 2002; 106(21): 2680 - 2686. [Abstract] [Full Text] [PDF]
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S. Jesmin, Y. Hattori, I. Sakuma, C. N. Mowa, and A. Kitabatake Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model Am J Physiol Heart Circ Physiol, October 1, 2002; 283 (4): H1387 - H1397. [Abstract] [Full Text] [PDF]
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A. Ceriello, C. Taboga, L. Tonutti, L. Quagliaro, L. Piconi, B. Bais, R. Da Ros, and E. Motz Evidence for an Independent and Cumulative Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Endothelial Dysfunction and Oxidative Stress Generation: Effects of Short- and Long-Term Simvastatin Treatment Circulation, September 3, 2002; 106(10): 1211 - 1218. [Abstract] [Full Text] [PDF]
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L. M. Semeniuk, A. J. Kryski, and D. L. Severson Echocardiographic assessment of cardiac function in diabetic db/db and transgenic db/db-hGLUT4 mice Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H976 - H982. [Abstract] [Full Text] [PDF]
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A. Ceriello, L. Quagliaro, B. Catone, R. Pascon, M. Piazzola, B. Bais, G. Marra, L. Tonutti, C. Taboga, and E. Motz Role of Hyperglycemia in Nitrotyrosine Postprandial Generation Diabetes Care, August 1, 2002; 25(8): 1439 - 1443. [Abstract] [Full Text] [PDF]
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 Y. Shizukuda and P. M. Buttrick Oxygen free radicals and heart failure: new insight into an old question Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L237 - L238. [Full Text] [PDF]
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L. B. Nielsen, E. D. Bartels, and E. Bollano Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice J. Biol. Chem., July 19, 2002; 277(30): 27014 - 27020. [Abstract] [Full Text] [PDF]
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L. Cai, W. Li, G. Wang, L. Guo, Y. Jiang, and Y. J. Kang Hyperglycemia-Induced Apoptosis in Mouse Myocardium: Mitochondrial Cytochrome c-Mediated Caspase-3 Activation Pathway Diabetes, June 1, 2002; 51(6): 1938 - 1948. [Abstract] [Full Text] [PDF]
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S. C. Smith Jr, D. Faxon, W. Cascio, H. Schaff, T. Gardner, A. Jacobs, S. Nissen, and R. Stouffer Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group VI: Revascularization in Diabetic Patients Circulation, May 7, 2002; 105 (18): e165 - e169. [Full Text] [PDF]
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H. Taegtmeyer, P. McNulty, and M. E. Young Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts Circulation, April 9, 2002; 105(14): 1727 - 1733. [Full Text] [PDF]
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