Melissa A Allwood1, Robert T Kinobe2, Laurel Ballantyne3, Nadya Romanova1, Luis G Melo3, Christopher A Ward3, Keith R Brunt4, Jeremy A Simpson5. 1. Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. 2. School of Veterinary & Biomedical Science, James Cook University, 1 James Cook Drive, Townsville, Queensland, 4811, Australia. 3. Department of Physiology, Queen's University, 99 University Avenue, Kingston, Ontario, K7L3N6, Canada. 4. Department of Pharmacology, Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John, New Brunswick, E2L 4L5, Canada. Electronic address: keith.brunt@dal.ca. 5. Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada. Electronic address: jeremys@uoguelph.ca.
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.
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-1transgenic 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-1transgenic mice had reduced capillary density, contractile reserve, and elevated end-diastolic pressure. However, HO-1transgenic mice had significantly attenuated ISO-induced cardiac dysfunction, interstitial fibrosis, and hypertrophy compared to control. Isolated cardiomyocytes from HO-1transgenic 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.
Authors: Melissa A Allwood; Brittany A Edgett; Ashley L Eadie; Jason S Huber; Nadya Romanova; Philip J Millar; Keith R Brunt; Jeremy A Simpson Journal: J Physiol Date: 2018-05-13 Impact factor: 5.182