title: Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload.
abstract: Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced α(1)-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice (n = 7), which was completely preserved in GRK3ct-AB mice (n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice (n = 11) displayed elevated end-diastolic pressure (8.5 ± 3.1 vs. 2.9 ± 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 ± 323 vs. 4,488 ± 342 μl/min, P < 0.05), and reduced dP/dt(max) and dP/dt(min) (both P < 0.05) compared with GRK3ct-AB mice (n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of β-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced β(1)-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload.
authors.affiliation: Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Norway.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: von Lueder
authors.forename: Jørgen
authors.initials: J
authors.lastname: Gravning
authors.forename: Ole-Jakob
authors.initials: OJ
authors.lastname: How
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vinge
authors.forename: Mohammed Shakil
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Krobert
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Terje S
authors.initials: TS
authors.lastname: Larsen
authors.forename: Otto A
authors.initials: OA
authors.lastname: Smiseth
authors.forename: Ellen
authors.initials: E
authors.lastname: Aasum
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D004719:Endomyocardial Fibrosis / Q000473:pathology; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006331:Heart Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006333:Heart Failure / Q000517:prevention & control; D006973:Hypertension / Q000150:complications*; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D054770:G-Protein-Coupled Receptor Kinase 3; D000262:Adenylyl Cyclases; D007545:Isoproterenol