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

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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.

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Abbreviations

AAR:

area at risk

eNOS:

Endothelial NO synthase

HR:

heart rate

I/R:

Ischemia/reperfusion

IS:

infarct size

LV:

left ventricular

MBP:

mean blood pressure

MI:

myocardial infarction

NO:

Nitric oxide

NT:

Nitrotyrosine

STZ:

Streptozotocin

TTC:

2,3,5-triphenyltetrazolium chloride

VEGF:

Vascular endothelial growth factor

WC:

Week control

WD:

Week diabetes

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Acknowledgements

The authors appreciate the contributions of Dr. Nai-tse Tsai. This work was supported by NIH grants HL70215 (RWC) and EY04618 (RBC).

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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta, GA, 30912, USA

    Guochuan Ma, John A. Johnson, Rahul Datar, Huda E. Tawfik, Dehuang Guo & R. William Caldwell

  2. Department of Cellular Biology & Anatomy, Medical College of Georgia, Augusta, GA, 30912, USA

    Mohamed Al-Shabrawey & Ruth B. Caldwell

  3. Department of Ophthalmology, Medical College of Georgia, Augusta, GA, 30912, USA

    Mohamed Al-Shabrawey & Ruth B. Caldwell

  4. Vascular Biology Center, Medical College of Georgia, Augusta, GA, 30912, USA

    Ruth B. Caldwell

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  1. Guochuan Ma
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  2. Mohamed Al-Shabrawey
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  3. John A. Johnson
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  4. Rahul Datar
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  5. Huda E. Tawfik
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  6. Dehuang Guo
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  7. Ruth B. Caldwell
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Correspondence to R. William Caldwell.

Additional information

Dr. Ma was on leave from the Sports Hospital, Sports Technical Institute of Guangdong, Guangzhou, China 510100. Dr. Al-Shabrawey is on leave from the Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

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Ma, G., Al-Shabrawey, M., Johnson, J.A. et al. Protection against myocardial ischemia/reperfusion injury by short-term diabetes: enhancement of VEGF formation, capillary density, and activation of cell survival signaling. Naunyn-Schmied Arch Pharmacol 373, 415–427 (2006). https://doi.org/10.1007/s00210-006-0102-1

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