title: Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure.
abstract: Previous studies have shown that loss of CD36 protects the heart from dysfunction induced by pressure overload in the presence of diet-induced insulin resistance and/or obesity. The beneficial effects of CD36 ablation in this context are mediated by preventing excessive cardiac fatty acid (FA) entry and reducing lipotoxic injury. However, whether or not the loss of CD36 can prevent pressure overload-induced cardiac dysfunction in the absence of chronic exposure to high circulating FAs is presently unknown. To address this, we utilized a tamoxifen-inducible cardiomyocyte-specific CD36 knockout (icCD36KO) mouse and genetically deleted CD36 in adulthood. Control mice (CD36 floxed/floxed mice) and icCD36KO mice were treated with tamoxifen and subsequently subjected to transverse aortic constriction (TAC) surgery to generate pressure overload-induced cardiac hypertrophy. Consistent with CD36 mediating a significant proportion of FA entry into the cardiomyocyte and subsequent FA utilization for ATP production, hearts from icCD36KO mice were metabolically inefficient and displayed signs of energetic stress, including activation of the energetic stress kinase, AMPK. In addition, impaired energetics in icCD36KO mice contributed to a rapid progression from compensated hypertrophy to heart failure. However, icCD36KO mice fed a medium-chain FA diet, whereby medium-chain FAs can enter into the cardiomyocyte independent from CD36, were protected from TAC-induced heart failure. Together these data suggest that limiting FA uptake and partial inhibition of FA oxidation in the heart via CD36 ablation may be detrimental for the compensated hypertrophic heart in the absence of sufficiently elevated circulating FAs to provide an adequate energy source.NEW & NOTEWORTHYLimiting CD36-mediated fatty acid uptake in the setting of obesity and/or insulin resistance protects the heart from cardiac hypertrophy and dysfunction. However, cardiomyocyte-specific CD36 ablation in the absence of elevated circulating fatty acid levels accelerates the progression of pressure overload-induced cardiac hypertrophy to systolic heart failure.
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Miranda M
authors.initials: MM
authors.lastname: Sung
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Nikole J
authors.initials: NJ
authors.lastname: Byrne
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Ty T
authors.initials: TT
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Jody
authors.initials: J
authors.lastname: Levasseur
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Grant
authors.initials: G
authors.lastname: Masson
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Boisvenue
authors.affiliation: Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.affiliation: Department of Pediatrics, Cardiovascular Research Centre, and Mazankowski Alberta Heart Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; and jason.dyck@ualberta.ca.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics*; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D004734:Energy Metabolism / Q000235:genetics; D004965:Estrogen Antagonists; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology*; D013629:Tamoxifen; D014280:Triglycerides / Q000097:blood
chemical_list: D018955:CD36 Antigens; D004965:Estrogen Antagonists; D014280:Triglycerides; D013629:Tamoxifen; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases
keywords: CD36; fatty-acid metabolism; heart failure; hypertrophy; pressure overload