title: Novel mechanisms for caspase inhibition protecting cardiac function with chronic pressure overload.
abstract: Myocyte apoptosis is considered a major mechanism in the pathogenesis of heart failure. Accordingly, manipulations that inhibit apoptosis are assumed to preserve cardiac function by maintaining myocyte numbers. We tested this assumption by examining the effects of caspase inhibition (CI) on cardiac structure and function in C57BL/6 mouse with pressure overload model induced by transverse aortic constriction (TAC). CI preserved left ventricular (LV) function following TAC compared with the vehicle. TAC increased apoptosis in non-myocytes more than in myocytes and these increases were blunted more in non-myocytes by CI. Total myocyte number, however, did not differ significantly among control and TAC groups and there was no correlation between myocyte number and apoptosis, but there was a strong correlation between myocyte number and an index of myocyte proliferation, Ki67-positive myocytes. Despite comparable pressure gradients, LV hypertrophy was less in the CI group, likely attributable to decreased wall stress. Since changes in myocyte numbers did not account for protection from TAC, several other CI-mediated mechanisms were identified including: (a) lessening of TAC-induced fibrosis, (b) augmentation of isolated myocyte contractility, and (c) increased angiogenesis and Ki67-positive myocytes, which were due almost entirely to the non-myocyte apoptosis, but not myocyte apoptosis, with CI. CI maintained LV function following TAC not by protecting against myocyte loss, but rather by augmenting myocyte contractile function, myocyte proliferation, and angiogenesis resulting in reduced LV wall stress, hypertrophy, and fibrosis.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA. parkmi@umdnj.edu
authors.forename: Misun
authors.initials: M
authors.lastname: Park
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Lin
authors.initials: L
authors.lastname: Yan
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Seunghun
authors.initials: S
authors.lastname: Yoon
authors.forename: Grace Jung Ah
authors.initials: GJ
authors.lastname: Lee
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.forename: Richard N
authors.initials: RN
authors.lastname: Kitsis
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018031:Connexin 43 / Q000032:analysis; D005355:Fibrosis; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control*; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D061945:Caspase Inhibitors; D018031:Connexin 43; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse