title: Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy.
abstract: Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA.
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Song
authors.forename: Albrecht G
authors.initials: AG
authors.lastname: Schmidt
authors.forename: Harvey S
authors.initials: HS
authors.lastname: Hahn
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Carr
authors.forename: Beate
authors.initials: B
authors.lastname: Frank
authors.forename: Luke
authors.initials: L
authors.lastname: Pater
authors.forename: Mike
authors.initials: M
authors.lastname: Gerst
authors.forename: Karen
authors.initials: K
authors.lastname: Young
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hoit
authors.forename: Bradley K
authors.initials: BK
authors.lastname: McConnell
authors.forename: Kobra
authors.initials: K
authors.lastname: Haghighi
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology*; D006332:Cardiomegaly / Q000235:genetics*; D002352:Carrier Proteins / Q000502:physiology; D018031:Connexin 43 / Q000032:analysis; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006333:Heart Failure / Q000517:prevention & control*; D020962:Heterotrimeric GTP-Binding Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D019703:Calcineurin; D002118:Calcium; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018031:Connexin 43; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D000099211:Phospholamban; D000099163:Myosin Binding Protein C