Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF-1alpha)-prolyl-4-hydroxylase 3 (PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat

Abstract Background Statins (HMG-CoA reductase inhibitors), are known to improve cardiac function in diabetes-induced cardiovascular disease. We investigated the mechanism by which statins ameliorate cardiac function after myocardial infarction (MI). Simvastatin (S) increased tube formation and migration of HUVEC in vitro . We examined the role of simvastatin on cardiac function in streptozotocin (STZ) induced diabetic rats subjected to MI. Methods Rats were randomly assigned to 1) Control (non-diabetic) Sham (CS); 2) Control (non-diabetic) MI (CMI); 3) Control Statin treated Sham (CSS); 4) Control Statin treated MI (CSMI); 5) Diabetic Sham (DS); 6) Diabetic MI (DMI); 7) Diabetic Statin treated Sham (DSS); 8) Diabetic Statin treated MI (DSMI). Two weeks after STZ/saline injection Simvastatin (1mg/kg.b.wt) was gavaged for 15days (d). MI was induced 30 d after treatment by permanent LAD ligation. Results The S treated MI groups exhibited increased arteriolar density (23±0.6 vs. 14.8±0.4 counts/mm 2 , DSMI vs. DMI) and reduced fibrosis at 30d post-MI. VEGF measurement by ELISA after 4d post-MI showed increased expression in DSMI group compared to DMI group. Western blot analysis showed decreased Prolyl-4-Hydroxylase 3 (PHD-3) in DSMI group as compared to DMI group. Echocardiographic analysis 4weeks after post-MI showed significant improvement in ejection fraction (50.11±1.83 vs. 32.46±2.19%; DSMI vs. DMI) and fractional shortening (26.77±1.12 vs.16.36±1.22%; DSMI vs. DMI) in both statin-treated MI groups regardless of diabetic status. Conclusion These results suggest that statin therapy mitigates impairment of angiogenesis and myocardial dysfunction following MI in the diabetic rat through PHD3 inhibition.