title: Heme oxygenase-1 induction improves cardiac function following myocardial ischemia by reducing oxidative stress.
abstract: BACKGROUND
  Oxidative stress plays a key role in exacerbating diabetes and cardiovascular disease. Heme oxygenase-1 (HO-1), a stress response protein, is cytoprotective, but its role in post myocardial infarction (MI) and diabetes is not fully characterized. We aimed to investigate the protection and the mechanisms of HO-1 induction in cardiomyocytes subjected to hypoxia and in diabetic mice subjected to LAD ligation.
  
  
  METHODS
  In vitro: cultured cardiomyocytes were treated with cobalt-protoporphyrin (CoPP) and tin protoporphyrin (SnPP) prior to hypoxic stress. In vivo: CoPP treated streptozotocin-induced diabetic mice were subjected to LAD ligation for 2/24 h. Cardiac function, histology, biochemical damage markers and signaling pathways were measured.
  
  
  RESULTS
  HO-1 induction lowered release of lactate dehydrogenase (LDH) and creatine phospho kinase (CK), decreased propidium iodide staining, improved cell morphology and preserved mitochondrial membrane potential in cardiomyocytes. In diabetic mice, Fractional Shortening (FS) was lower than non-diabetic mice (35±1%vs.41±2, respectively p<0.05). CoPP-treated diabetic animals improved cardiac function (43±2% p<0.01), reduced CK, Troponin T levels and infarct size compared to non-treated diabetic mice (P<0.01, P<0.001, P<0.01 respectively). CoPP-enhanced HO-1 protein levels and reduced oxidative stress in diabetic animals, as indicated by the decrease in superoxide levels in cardiac tissues and plasma TNFα levels (p<0.05). The increased levels of HO-1 by CoPP treatment after LAD ligation led to a shift of the Bcl-2/bax ratio towards the antiapoptotic process (p<0.05). CoPP significantly increased the expression levels of pAKT and pGSK3β (p<0.05) in cardiomyocytes and in diabetic mice with MI. SnPP abolished CoPP's cardioprotective effects.
  
  
  CONCLUSIONS
  HO-1 induction plays a role in cardioprotection against hypoxic damage in cardiomyocytes and in reducing post ischemic cardiac damage in the diabetic heart as proved by the increased levels of pAKT with a concomitant inhibition of pGSK3β leading to preserved mitochondrial membrane potential.
authors.affiliation: Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University, Petah-Tikva, Israel.
authors.forename: Yossi
authors.initials: Y
authors.lastname: Issan
authors.affiliation: Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University, Petah-Tikva, Israel; Cardiology Department, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Kornowski
authors.affiliation: Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University, Petah-Tikva, Israel; Cardiac Surgery department, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Aravot
authors.affiliation: Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Michal
authors.initials: M
authors.lastname: Laniado-Schwartzman
authors.affiliation: Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, United States of America.
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.affiliation: Department of Internal Medicine, Marshall University Joan C. Edwards School of Medicine, Huntington, West Virginia, United States of America.
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.affiliation: Cardiac Research Laboratory, Felsenstein Medical Research Institute, Tel-Aviv University, Petah-Tikva, Israel; Cardiac Surgery department, Rabin Medical Center, Tel-Aviv University, Petah-Tikva, Israel.
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008665:Metalloporphyrins / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: D008665:Metalloporphyrins; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt