title: 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 15 days (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 30 d 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 4 weeks 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.
  
  
  CONCLUSIONS
  These results suggest that statin therapy mitigates impairment of angiogenesis and myocardial dysfunction following MI in the diabetic rat through PHD3 inhibition.
authors.affiliation: Department of Surgery, Molecular Cardiology and Angiogenesis Laboratory, University of Connecticut Health Center, Farmington, CT, USA. Electronic address: mthirunavukkarasu@uchc.edu.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Thirunavukkarasu
authors.forename: Vaithinathan
authors.initials: V
authors.lastname: Selvaraju
authors.forename: Nageswara Rao
authors.initials: NR
authors.lastname: Dunna
authors.forename: Jocelyn L C
authors.initials: JL
authors.lastname: Foye
authors.forename: Mandip
authors.initials: M
authors.lastname: Joshi
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology*; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use*; D013311:Streptozocin
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064800:Prolyl-Hydroxylase Inhibitors; D013311:Streptozocin; D019821:Simvastatin
keywords: Diabetes; Myocardial infarction; Prolyl-hydroxylase; Statin; VEGF