Abstract 327: Inhibition of Cardiac Myocyte Gq Signaling in High Blood Pressure Improves Cardiac Remodeling and Beta-Adrenergic Receptor Response
Chronic ventricular pressure overload states and elevated levels of neurohormones(catecholamines, AngII) initiate cardiac hypertrophy and dysfunction and can bind to certain Gq-coupled 7-transmembrane receptors. The goal of the current study was to determine the role of endogenous cardiac myocyte Gq signaling and its role in cardiac hypertrophy and dysfunction during high blood pressure (HBP) induced by renal stenosis (2K1C).
Methods and Results: We induced HBP for 8 wks in control and mice expressing an inhibitor peptide of Gq signaling (GqI). Echo showed that GqI mice had improved cardiac function (~20%), but no alterations in cardiac or myocyte hypertrophy compared to controls. However, GqI did decrease mRNA levels of cardiac remodeling genes such as MMP3, periostin, Adamts 2 and 8, and tenascin C compared to controls after 2K1C. Chronic treatment with metoprolol removed the benefit of GqI following HBP. GqI mice had a greater response in ejection fraction (82±2.8% vs. 67±2.4%, n=7) with acute injection of isoproterenol. Since the 2K1C model has high plasma levels of AngII and norepinephrine and AngII effects on cardiac myocytes are not well understood, we used our vascular smooth muscle GqI line to study the effects of dual stimulation of these receptors on beta adrenergic receptor function. Abdominal aortic rings were dissected out, endothelium was denuded and a dose response to isoproterenol was performed as well as isoproterenol with AngII. Both control and GqI rings had similar responses to isoproterenol. However, in the presence of AngII, GqI rings had a greater beta adrenergic mediated relaxation to isoproterenol versus control.
Conclusions: These data suggest that in the 2K1C model of HBP Gq signaling inhibits beta adrenergic mediated responses. Furthermore, these data show that one beneficial effect of common therapeutics such as AngII receptor antagonists may be the improvement in beta adrenergic signaling.
This research has received full or partial funding support from the American Heart Association, AHA National Center.