title: The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia-reperfusion injury.
abstract: OBJECTIVE
  Ischemia-reperfusion (I/R) injury, often encountered clinically, results in myocardial apoptosis and necrosis. Hydrogen sulfide (H(2)S) is produced endogenously in response to ischemia and thought to be cardioprotective, although its mechanism of action is not fully known. This study investigates cardioprotection provided by exogenous H2S, generated as sodium sulfide on apoptosis following myocardial I/R injury.
  
  
  METHODS
  The mid-LAD coronary artery in Yorkshire swine (n=12) was occluded for 60 min, followed by reperfusion for 120 min. Controls (n=6) received placebo, and treatment animals (n=6) received sulfide 10 min prior to and throughout reperfusion. Hemodynamic, global, and regional functional measurements were obtained. Evans blue/TTC staining identified the area-at-risk (AAR) and infarction. Serum CK-MB, troponin I, and FABP were assayed. Tissue expression of bcl-2, bad, apoptosis-inducing-factor (AIF), total and cleaved caspase-3, and total and cleaved PARP were assessed. PAR and TUNEL staining were performed to assess apoptotic cell counts and poly-ADP ribosylation, respectively.
  
  
  RESULTS
  Pre-I/R hemodynamics were similar between groups. Post-I/R, mean arterial pressure (mmHg) was reduced by 30.2+/-4.3 in controls vs 8.2+/-6.9 in treatment animals (p=0.01). +LV dP/dt (mmHg/s) was reduced by 1308+/-435 in controls vs 403+/-283 in treatment animals (p=0.001). Infarct size (% of AAR) in controls was 47.4+/-6.2% vs 20.1+/-3.3% in the treated group (p=0.003). In treated animals, CK-MB and FABP were lower by 47.0% (p=0.10) and 45.1% (p=0.01), respectively. AIF, caspase-3, and PARP expression was similar between groups, whereas cleaved caspase-3 and cleaved PARP was lower in treated animals (p=0.04). PAR staining was significantly reduced in sulfide treated groups (p=0.04). TUNEL staining demonstrated significantly fewer apoptotic cells in sulfide treated animals (p=0.02).
  
  
  CONCLUSIONS
  Sodium sulfide is efficacious in reducing apoptosis in response to I/R injury. Along with its known effects on reducing necrosis, sulfide's effects on apoptosis may partially contribute to providing myocardial protection. Exogenous sulfide may have therapeutic utility in clinical settings in which I/R injury is encountered.
authors.affiliation: Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
authors.forename: Neel R
authors.initials: NR
authors.lastname: Sodha
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Eszter M
authors.initials: EM
authors.lastname: Horvath
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3 / Q000032:analysis; D052279:Creatine Kinase, MB Form / Q000097:blood; D050556:Fatty Acid-Binding Proteins / Q000097:blood; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000097:blood / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000473:pathology* / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis; D013440:Sulfides / Q000627:therapeutic use*; D013552:Swine; D019210:Troponin I / Q000097:blood; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
chemical_list: D015415:Biomarkers; D050556:Fatty Acid-Binding Proteins; D013440:Sulfides; D019210:Troponin I; D011065:Poly(ADP-ribose) Polymerases; D052279:Creatine Kinase, MB Form; D053148:Caspase 3; C033479:sodium sulfide