Document Detail

Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.
MedLine Citation:
PMID:  20404253     Owner:  NLM     Status:  MEDLINE    
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.
METHODS AND 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.
Guangwu Wang; Tariq Hamid; Rachel J Keith; Guihua Zhou; Charles R Partridge; Xilin Xiang; Justin R Kingery; Robert K Lewis; Qianhong Li; D Gregg Rokosh; Rachael Ford; Francis G Spinale; Daniel W Riggs; Sanjay Srivastava; Aruni Bhatnagar; Roberto Bolli; Sumanth D Prabhu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-04-19
Journal Detail:
Title:  Circulation     Volume:  121     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-04     Completed Date:  2010-05-24     Revised Date:  2013-03-27    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1912-25     Citation Subset:  AIM; IM    
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.
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MeSH Terms
Apoptosis / physiology*
Carbon Monoxide / metabolism
Cardiotonic Agents / pharmacology
Chronic Disease
Gene Expression / physiology
Heart Failure / drug therapy,  pathology*,  physiopathology*
Heme Oxygenase-1 / genetics*,  metabolism*
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria / physiology
Myocardial Infarction / drug therapy,  pathology,  physiopathology
Myocardium / metabolism,  pathology
Neovascularization, Physiologic / physiology
Organometallic Compounds / pharmacology
Oxidative Stress / physiology
Stroke Volume / physiology
Up-Regulation / physiology
Ventricular Dysfunction, Left / drug therapy,  pathology,  physiopathology
Ventricular Remodeling / physiology
Grant Support
ES-11860/ES/NIEHS NIH HHS; HL-55477/HL/NHLBI NIH HHS; HL-55757/HL/NHLBI NIH HHS; HL-70897/HL/NHLBI NIH HHS; HL-76794/HL/NHLBI NIH HHS; HL-78825/HL/NHLBI NIH HHS; P01 ES011860-050004/ES/NIEHS NIH HHS; P01 HL078825-040002/HL/NHLBI NIH HHS; R01 HL055477-10A1/HL/NHLBI NIH HHS; R01 HL059378-13/HL/NHLBI NIH HHS; R01 HL070897/HL/NHLBI NIH HHS; R01 HL070897-04/HL/NHLBI NIH HHS; R01 HL076794/HL/NHLBI NIH HHS; R01 HL076794-04/HL/NHLBI NIH HHS; R01 HL099014-01/HL/NHLBI NIH HHS; R01 HL099014-02/HL/NHLBI NIH HHS; R37 HL055757/HL/NHLBI NIH HHS; R37 HL055757-14/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Cardiotonic Agents; 0/Organometallic Compounds; 0/tricarbonylchloro(glycinato)ruthenium(II); 630-08-0/Carbon Monoxide; EC Oxygenase-1

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