Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice

Melissa A. Allwood, Robert T. Kinobe, Laurel Ballantyne, Nadya Romanova, Luis G. Melo, Christopher A. Ward, Keith R. Brunt, Jeremy A. Simpson

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Introduction Heme oxygenase-1 (HO-1) is a cytoprotective enzyme induced by stress. Heart failure is a condition of chronic stress-induced remodeling and is often accompanied by comorbidities such as age and hypertension. HO-1 is known to be protective in the setting of acute myocardial infarction. The role of HO-1 in heart failure is not known, particularly in the setting of pressure overload. Methods Mice with alpha-myosin heavy chain restricted expression of HO-1 were aged for 1 year. In addition, mice underwent transverse aortic constriction (TAC) or were infused with isoproterenol (ISO) to induce heart failure. Results HO-1 transgenic mice developed spontaneous heart failure after 1 year compared to their wild-type littermates and showed accelerated cardiac dysfunction 2 weeks following TAC. Wild-type mice undergoing pressure overload demonstrated extensive interstitial fibrosis that was prevented by HO-1 overexpression, yet HO-1 transgenic mice had reduced capillary density, contractile reserve, and elevated end-diastolic pressure. However, HO-1 transgenic mice had significantly attenuated ISO-induced cardiac dysfunction, interstitial fibrosis, and hypertrophy compared to control. Isolated cardiomyocytes from HO-1 transgenic mice treated with ISO did not show evidence of hypercontracture/necrosis and had reduced NADH oxidase activity. Conclusions HO-1 is an effective mechanism for reducing acute myocardial stress such as excess beta-adrenergic activity. However, in our age and pressure overload models, HO-1 showed detrimental rather than therapeutic effects in the development of heart failure.

Original languageEnglish
Pages (from-to)231-237
Number of pages7
JournalCardiovascular Pathology
Volume23
Issue number4
DOIs
Publication statusPublished - 2014

Bibliographical note

Funding Information:
Funding: This work was funded in part by grants from the Canadian Institutes of Health Research (Grants # MOP111159) (JAS) and Heart and Stroke Foundation of Canada (Grant # NA5779) (CAW & LGM). JAS is a New Investigator of the Heart and Stroke Foundation of Ontario.

ASJC Scopus Subject Areas

  • Pathology and Forensic Medicine
  • Cardiology and Cardiovascular Medicine

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