title: Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.
abstract: BACKGROUND
  Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling.
  
  
  RESULTS
  Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis.
  
  
  CONCLUSIONS
  HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.
authors.affiliation: Division of Cardiovascular Medicine, Institute of Molecular Cardiology, Department of Medicine, University of Louisville, ACB, Third Floor, 550 S Jackson St, Louisville, KY 40202, USA.
authors.forename: Guangwu
authors.initials: G
authors.lastname: Wang
authors.forename: Tariq
authors.initials: T
authors.lastname: Hamid
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Keith
authors.forename: Guihua
authors.initials: G
authors.lastname: Zhou
authors.forename: Charles R
authors.initials: CR
authors.lastname: Partridge
authors.forename: Xilin
authors.initials: X
authors.lastname: Xiang
authors.forename: Justin R
authors.initials: JR
authors.lastname: Kingery
authors.forename: Robert K
authors.initials: RK
authors.lastname: Lewis
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Li
authors.forename: D Gregg
authors.initials: DG
authors.lastname: Rokosh
authors.forename: Rachael
authors.initials: R
authors.lastname: Ford
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Riggs
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002908:Chronic Disease; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
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