title: Heme oxygenase-1 overexpression exacerbates heart failure with aging and pressure overload but is protective against isoproterenol-induced cardiomyopathy in mice.
abstract: BACKGROUND
  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.
authors.affiliation: Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Allwood
authors.affiliation: School of Veterinary & Biomedical Science, James Cook University, 1 James Cook Drive, Townsville, Queensland, 4811, Australia.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kinobe
authors.affiliation: Department of Physiology, Queen's University, 99 University Avenue, Kingston, Ontario, K7L3N6, Canada.
authors.forename: Laurel
authors.initials: L
authors.lastname: Ballantyne
authors.affiliation: Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
authors.forename: Nadya
authors.initials: N
authors.lastname: Romanova
authors.affiliation: Department of Physiology, Queen's University, 99 University Avenue, Kingston, Ontario, K7L3N6, Canada.
authors.forename: Luis G
authors.initials: LG
authors.lastname: Melo
authors.affiliation: Department of Physiology, Queen's University, 99 University Avenue, Kingston, Ontario, K7L3N6, Canada.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ward
authors.affiliation: Department of Pharmacology, Dalhousie Medicine New Brunswick, 100 Tucker Park Road, Saint John, New Brunswick, E2L 4L5, Canada. Electronic address: keith.brunt@dal.ca.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Brunt
authors.affiliation: 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.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000150:complications; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D011994:Recombinant Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D007545:Isoproterenol
keywords: Angiogenesis; Bradycardia; Cardiac remodeling; Hemodynamics; Histology; Myocardial infarction