Protection against myocardial ischemia/reperfusion injury by short-term diabetes: Enhancement of VEGF formation, capillary density, and activation of cell survival signaling

Guochuan Ma, Mohamed Al-Shabrawey, John A Johnson, Rahul Datar, Huda El Sayed Tawfik, Dehuang Guo, Ruth B Caldwell, Robert William Caldwell

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Abstract

The aims of this study were to determine effects of diabetes duration on myocardial ischemia/reperfusion (I/R) injury and test whether time-dependent differences in sensitivity of the streptozotocin diabetic rat heart to I/R are related to differences in vascular density, levels of vascular endothelial growth factor (VEGF) or endothelial nitric oxide synthase (eNOS) expression, NO formation, activation of Akt, and/or oxidative stress. After 2 or 6 weeks of streptozotocin-induced diabetes, I/R injury was induced by occlusion (30 min) and reperfusion of the left descending coronary artery. After 2 weeks of diabetes, infarct size and cleavage of caspase-3, a proapoptosis signal, were decreased as compared with normoglycemic controls or rats that had been diabetic for 6 weeks, whereas capillary density and levels of VEGF and eNOS protein and cardiac NOx levels were all increased. Phosphorylation of Akt, a prosurvival signal, was also significantly increased after 2 weeks of diabetes. Cardiac lipid peroxidation was comparable to controls after 2 weeks of diabetes, whereas levels of nitrotyrosine, a peroxynitrite biomarker, were reduced. After 6 weeks of diabetes, lipid peroxidation was increased and levels of VEGF and plasma NO were reduced as compared with controls or rats diabetic for 2 weeks. Our results indicate endogenous cardioprotective mechanisms become transiently activated in this early stage of diabetes and that this may protect the heart from I/R injury through enhancement of VEGF and eNOS expression, NO formation, activation of cell survival signals, and decreased oxidative stress.

Original languageEnglish (US)
Pages (from-to)415-427
Number of pages13
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume373
Issue number6
DOIs
StatePublished - Sep 1 2006

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Myocardial Reperfusion Injury
Reperfusion Injury
Vascular Endothelial Growth Factor A
Myocardial Ischemia
Nitric Oxide Synthase Type III
Cell Survival
Lipid Peroxidation
Reperfusion
Oxidative Stress
Peroxynitrous Acid
Experimental Diabetes Mellitus
Streptozocin
Caspase 3
Blood Vessels
Coronary Vessels
Ischemia
Biomarkers
Phosphorylation
Proteins

Keywords

  • Diabetes
  • Heart
  • Ischemia/reperfusion
  • Oxidative stress
  • Preconditioning
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Protection against myocardial ischemia/reperfusion injury by short-term diabetes: Enhancement of VEGF formation, capillary density, and activation of cell survival signaling",
abstract = "The aims of this study were to determine effects of diabetes duration on myocardial ischemia/reperfusion (I/R) injury and test whether time-dependent differences in sensitivity of the streptozotocin diabetic rat heart to I/R are related to differences in vascular density, levels of vascular endothelial growth factor (VEGF) or endothelial nitric oxide synthase (eNOS) expression, NO formation, activation of Akt, and/or oxidative stress. After 2 or 6 weeks of streptozotocin-induced diabetes, I/R injury was induced by occlusion (30 min) and reperfusion of the left descending coronary artery. After 2 weeks of diabetes, infarct size and cleavage of caspase-3, a proapoptosis signal, were decreased as compared with normoglycemic controls or rats that had been diabetic for 6 weeks, whereas capillary density and levels of VEGF and eNOS protein and cardiac NOx levels were all increased. Phosphorylation of Akt, a prosurvival signal, was also significantly increased after 2 weeks of diabetes. Cardiac lipid peroxidation was comparable to controls after 2 weeks of diabetes, whereas levels of nitrotyrosine, a peroxynitrite biomarker, were reduced. After 6 weeks of diabetes, lipid peroxidation was increased and levels of VEGF and plasma NO were reduced as compared with controls or rats diabetic for 2 weeks. Our results indicate endogenous cardioprotective mechanisms become transiently activated in this early stage of diabetes and that this may protect the heart from I/R injury through enhancement of VEGF and eNOS expression, NO formation, activation of cell survival signals, and decreased oxidative stress.",
keywords = "Diabetes, Heart, Ischemia/reperfusion, Oxidative stress, Preconditioning, Vascular endothelial growth factor",
author = "Guochuan Ma and Mohamed Al-Shabrawey and Johnson, {John A} and Rahul Datar and Tawfik, {Huda El Sayed} and Dehuang Guo and Caldwell, {Ruth B} and Caldwell, {Robert William}",
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T1 - Protection against myocardial ischemia/reperfusion injury by short-term diabetes

T2 - Enhancement of VEGF formation, capillary density, and activation of cell survival signaling

AU - Ma, Guochuan

AU - Al-Shabrawey, Mohamed

AU - Johnson, John A

AU - Datar, Rahul

AU - Tawfik, Huda El Sayed

AU - Guo, Dehuang

AU - Caldwell, Ruth B

AU - Caldwell, Robert William

PY - 2006/9/1

Y1 - 2006/9/1

N2 - The aims of this study were to determine effects of diabetes duration on myocardial ischemia/reperfusion (I/R) injury and test whether time-dependent differences in sensitivity of the streptozotocin diabetic rat heart to I/R are related to differences in vascular density, levels of vascular endothelial growth factor (VEGF) or endothelial nitric oxide synthase (eNOS) expression, NO formation, activation of Akt, and/or oxidative stress. After 2 or 6 weeks of streptozotocin-induced diabetes, I/R injury was induced by occlusion (30 min) and reperfusion of the left descending coronary artery. After 2 weeks of diabetes, infarct size and cleavage of caspase-3, a proapoptosis signal, were decreased as compared with normoglycemic controls or rats that had been diabetic for 6 weeks, whereas capillary density and levels of VEGF and eNOS protein and cardiac NOx levels were all increased. Phosphorylation of Akt, a prosurvival signal, was also significantly increased after 2 weeks of diabetes. Cardiac lipid peroxidation was comparable to controls after 2 weeks of diabetes, whereas levels of nitrotyrosine, a peroxynitrite biomarker, were reduced. After 6 weeks of diabetes, lipid peroxidation was increased and levels of VEGF and plasma NO were reduced as compared with controls or rats diabetic for 2 weeks. Our results indicate endogenous cardioprotective mechanisms become transiently activated in this early stage of diabetes and that this may protect the heart from I/R injury through enhancement of VEGF and eNOS expression, NO formation, activation of cell survival signals, and decreased oxidative stress.

AB - The aims of this study were to determine effects of diabetes duration on myocardial ischemia/reperfusion (I/R) injury and test whether time-dependent differences in sensitivity of the streptozotocin diabetic rat heart to I/R are related to differences in vascular density, levels of vascular endothelial growth factor (VEGF) or endothelial nitric oxide synthase (eNOS) expression, NO formation, activation of Akt, and/or oxidative stress. After 2 or 6 weeks of streptozotocin-induced diabetes, I/R injury was induced by occlusion (30 min) and reperfusion of the left descending coronary artery. After 2 weeks of diabetes, infarct size and cleavage of caspase-3, a proapoptosis signal, were decreased as compared with normoglycemic controls or rats that had been diabetic for 6 weeks, whereas capillary density and levels of VEGF and eNOS protein and cardiac NOx levels were all increased. Phosphorylation of Akt, a prosurvival signal, was also significantly increased after 2 weeks of diabetes. Cardiac lipid peroxidation was comparable to controls after 2 weeks of diabetes, whereas levels of nitrotyrosine, a peroxynitrite biomarker, were reduced. After 6 weeks of diabetes, lipid peroxidation was increased and levels of VEGF and plasma NO were reduced as compared with controls or rats diabetic for 2 weeks. Our results indicate endogenous cardioprotective mechanisms become transiently activated in this early stage of diabetes and that this may protect the heart from I/R injury through enhancement of VEGF and eNOS expression, NO formation, activation of cell survival signals, and decreased oxidative stress.

KW - Diabetes

KW - Heart

KW - Ischemia/reperfusion

KW - Oxidative stress

KW - Preconditioning

KW - Vascular endothelial growth factor

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