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Cardioprotective and Antiapoptotic Effects of Heme Oxygenase-1 in the Failing Heart
Open accessAbstract
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 μL), 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 H 2 O 2 -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.
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“In vivo, overexpression of cardiomyocyte-targeted HO-1 improved survival after myocardial infarction by reducing myocyte-specific apoptosis and postinfarction left ventricular remodeling, in part, by preserving mitochondrial function (440).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [440]
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Metadata
- Authors
- Wang, G., Hamid, T., Keith, R. J., Zhou, G., Partridge, C. R., Xiang, X., Kingery, J. R., Lewis, R. K., Li, Q., Rokosh, D. G., Ford, R., Spinale, F. G., Riggs, D. W., Srivastava, S., Bhatnagar, A., Bolli, R., & Prabhu, S. D.
- Affiliations
- University of Louisville (US)
- From the Institute of Molecular Cardiology, Department of Medicine, University of Louisville (G.W., T.H., R.J.K., G.Z., C.R.P., X.X., J.R.K., R.K.L., Q.L., D.G.R., D.W.R., S.S., A.B., R.B., S.D.P.) and Louisville Veterans Affairs Medical Center, Louisville, Ky (S.D.P.); and Department of Surgery, Medical University of South Carolina, Charleston (R.F., F.G.S.).
- ORCID
- Venue
- Circulation
- Published
- 2010-05-04
- Volume
- 121
- Issue
- 17
- Pages
- 1912-1925
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2917269
- OpenAlex
- W2052867135
- Cited by
- 249
- References
- 38
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 10 · 2023: 9 · 2022: 14 · 2021: 16 · 2020: 12 · 2019: 18 · 2018: 13 · 2017: 17 · 2016: 12 · 2015: 16 · 2014: 23 · 2013: 26 · 2012: 21
- FWCI
- 9.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL078825, R01HL070897, R01HL059378, R37HL055757, HL 78825, HL 55757, HL-76794, R01HL099014, R01HL055757, R01HL055477, HL70897, HL55477, R01HL076794)
- National Institute of Environmental Health Sciences ((ES11860, P01ES011860)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- heme oxygenase-1, chronic heart failure, cardiac remodeling, cardiomyocyte apoptosis, carbon monoxide, mitochondrial permeability transition, p53, oxidative stress, myocardial fibrosis, cardiomyocyte hypertrophy, CORM-3, myocardial neovascularization, myocardial infarction, cardioprotection, malondialdehyde
- MeSH terms
- Animals, Carbon Monoxide, Cardiotonic Agents, Chronic Disease, Fibrosis, Heart Failure, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Myocardial Infarction, Myocardium, Organometallic Compounds, Stroke Volume, Up-Regulation, Gene Expression, Apoptosis, Oxidative Stress, Ventricular Dysfunction, Left, Neovascularization, Physiologic, Ventricular Remodeling, Mice, Heme Oxygenase-1
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