Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.
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.
Wang
Guangwu
G
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.
Hamid
Tariq
T
Keith
Rachel J
RJ
Zhou
Guihua
G
Partridge
Charles R
CR
Xiang
Xilin
X
Kingery
Justin R
JR
Lewis
Robert K
RK
Li
Qianhong
Q
Rokosh
D Gregg
DG
Ford
Rachael
R
Spinale
Francis G
FG
Riggs
Daniel W
DW
Srivastava
Sanjay
S
Bhatnagar
Aruni
A
Bolli
Roberto
R
Prabhu
Sumanth D
SD
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
D002316:Cardiotonic Agents; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
Circulation. 2007 Oct 2;116(14):1577-84
17785622
Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1029-37
11076792
Circulation. 2009 Mar 17;119(10):1386-97
19255345
J Mol Med (Berl). 2007 Nov;85(11):1175-86
17589818
Nat Med. 2001 Jun;7(6):693-8
11385506
J Mol Cell Cardiol. 2005 Jan;38(1):135-43
15623430
Circ Res. 2009 Oct 9;105(8):793-802
19729598
Nat Med. 2002 Mar;8(3):240-6
11875494
Biochem Biophys Res Commun. 2006 Apr 14;342(3):984-90
16598857
Circulation. 2001 Mar 27;103(12):1695-701
11273999
J Clin Invest. 1995 Dec;96(6):2676-82
8675634
J Clin Invest. 2003 May;111(10):1497-504
12750399
Oncogene. 1994 Jun;9(6):1799-805
8183579
Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1290-5
15528225
J Mol Cell Cardiol. 2007 Jan;42(1):150-8
17070837
Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H48-59
17322421
J Immunol. 2001 Mar 15;166(6):4185-94
11238670
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10925-30
9380736
J Mol Cell Cardiol. 2002 Oct;34(10):1357-65
12392996
Cardiovasc Res. 2002 Aug 1;55(2):396-405
12123779
Cardiovasc Res. 2005 Jul 1;67(1):21-9
15896727
Cardiovasc Res. 2007 Jun 1;74(3):445-55
17362897
Basic Res Cardiol. 2009 Mar;104(2):181-8
19242640
Biophys J. 1999 Jan;76(1 Pt 1):469-77
9876159
J Exp Med. 2000 Oct 2;192(7):1015-26
11015442
J Mol Cell Cardiol. 1999 Aug;31(8):1581-9
10423355
Am J Physiol Heart Circ Physiol. 2003 Feb;284(2):H549-58
12388276
J Clin Invest. 2005 Mar;115(3):565-71
15765138
Circ Res. 2000 Jun 23;86(12):1224-9
10864912
Free Radic Biol Med. 2005 Jul 1;39(1):1-25
15925276
Biochem Pharmacol. 2006 Jan 12;71(3):307-18
16329999
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10919-24
9380735
Circ Res. 2003 Jul 25;93(2):e2-8
12842916
J Pathol. 2002 Jun;197(2):230-7
12015748
Circulation. 2002 Feb 5;105(5):602-7
11827926
Circ Res. 2001 Jul 20;89(2):168-73
11463724
Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3673-84
17921335