Protection against myocardial ischemia/reperfusion injury by short-term diabetes: enhancement of VEGF formation, capillary density, and activation of cell survival signaling.
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 NO(x) 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.
Ma
Guochuan
G
Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA, 30912, USA.
Al-Shabrawey
Mohamed
M
Johnson
John A
JA
Datar
Rahul
R
Tawfik
Huda E
HE
Guo
Dehuang
D
Caldwell
Ruth B
RB
Caldwell
R William
RW
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D002196:Capillaries / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D003326:Coronary Circulation / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D053148:Caspase 3