title: Mechanisms of angiotensin II-dependent progression to heart failure.
abstract: Up-regulation of angiotensin II (AII) signalling plays an important role in the pathogenesis of cardiac hypertrophy and failure as evidenced by the efficacy of AII receptor blockers or inhibitors of AII biosynthesis in reversing ventricular hypertrophy and preventing human heart failure. The mechanisms underlying AII action in the heart remain undefined. Myocardial-specific expression of the AII type 1 receptor (AT1R) in mice is sufficient for inducing progressive myocyte hypertrophy and cardiac remodelling leading to adult heart failure with a disease progression course reminiscent of work overload-induced human heart failure. We examined the functional, structural and genetic changes associated with disease progression in this model. The results reveal that AT1R-dependent interaction between myocytes and non-myocytes is critical in cardiac remodelling. At the level of cardiomyocytes, decreased mitochondrial function is one of the earliest events of AII action leading to mitochondrial depletion and increased apoptosis. Up-regulation of cardiac Bcl-2 prevents mitochondrial deterioration, cardiomyocyte loss and pathologic remodelling. Importantly, Bcl-2 completely rescues premature death due to heart failure and maintains the 'compensated' state. The data suggest that targeting Bcl-2 or interfering with mitochondrial dysfunction may offer new therapeutic opportunities for preventing transition from compensated hypertrophy to heart failure.
authors.affiliation: Research Unit in Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal (IRCM), 110 Avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada.
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.forename: Nassim
authors.initials: N
authors.lastname: Dali-Youcef
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Anne
authors.initials: A
authors.lastname: Aries
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D006331:Heart Diseases / Q000473:pathology*; D006333:Heart Failure / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D000804:Angiotensin II