Abstract 16086: Simvastatin Treatment Inhibits Hypoxia Inducible Factor 1-Alpha-(Hif-1Alpha)-Prolyl-4-Hydroxylase 3 (phd-3) and Increases Angiogenesis in Streptozotocin-Induced Diabetic Rat Myocardium
Statins (HMG-CoA reductase inhibitors), are known to improve cardiac function in diabetes-induced cardiovascular disease as a result of their antioxidant capacities. Oxidative stress plays a key role in the pathogenesis of several vascular complications in diabetes mellitus leading to endothelial dysfunction. We evaluated the role of the simvastatin (S) on cardiac endothelial function in streptozotocin (STZ) induced diabetic rats subjected to myocardial infarction (MI).
Methods: Male Sprague-Dawley rats (300-325g) were randomized (n=20 per group) to receive an intraperitoneal injection of saline or STZ (65 mg/kg b.wt). Hyperglycemia was documented by tail-vein glucose with a glucometer in STZ treated animals. Rats with blood glucose 300 mg/dL and control rats were randomly assigned to 1) Non diabetic (ND) Sham (NDS); 2) NDMI; 3) ND S Sham (NDSS); 4) ND S MI (NDSMI); 5) diabetic Sham (DS); 6) DMI; 7) D S Sham (DSS); 8) D S MI (DSMI). Simvastatin (1mg/kg b.wt) was gavaged for 15 days (d) after 15 days of STZ or saline injection. MI was induced 30 days after STZ or saline by permanent LAD ligation.
Results: Compared with untreated animals, the S treated MI groups exhibited increased myocardial arteriolar density (23±3 vs 15 ± 1.7; counts/mm2, P<0.05, DSMI vs DMI) and reduced fibrosis at 7 d post-MI. Western blot analysis at 4 d post-MI showed increased expression (1.5 fold) of vascular endothelial growth factor and decreased (1.7 fold) PHD-3 in the DSMI vs DMI group. Echocardiographic analysis at 4 weeks post-MI showed significant improvement in ejection fraction (50±1.8 vs 32±2.2 %; P<0.05, DSMI vs DMI) and fractional shortening (26±1.1 vs 16±1.2 %; P<0.05, DSMI vs DMI) in both statin-treated MI groups regardless of diabetic status.
Conclusion: In diabetic rats, statin therapy appears to mitigate myocardial dysfunction and impairment of angiogenesis through PHD3 inhibition following MI. This is the first report to reveal a new role for statins in diabetes- induced cardiovascular disease.
- © 2011 by American Heart Association, Inc.