Carvedilol induces biased β1 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility. Issue 10 (21st September 2020)

• Record Type: Journal Article
• Authors: Wang, Qingtong; Wang, Ying; West, Toni M; Liu, Yongming; Reddy, Gopireddy R; Barbagallo, Federica; Xu, Bing; Shi, Qian; Deng, Bingqing; Wei, Wei; Xiang, Yang K
• Is Part Of: Cardiovascular research. Volume 117:Issue 10(2021)
• Page Start: 2237
• Page End: 2251
• Publication Date: 2020-09-21
• Subjects: Carvedilol -- Cyclic guanosine monophosphate -- Heart dysfunction -- β adrenergic receptor -- Contractility; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvaa266
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: β-blockers are widely used in therapy for heart failure and hypertension. β-blockers are also known to evoke additional diversified pharmacological and physiological effects in patients. We aim to characterize the underlying molecular signalling and effects on cardiac inotropy induced by β-blockers in animal hearts. Methods and results: Wild-type mice fed high-fat diet (HFD) were treated with carvedilol, metoprolol, or vehicle and echocardiogram analysis was performed. Heart tissues were used for biochemical and histological analyses. Cardiomyocytes were isolated from normal and HFD mice and rats for analysis of adrenergic signalling, calcium handling, contraction, and western blot. Biosensors were used to measure β-blocker-induced cyclic guanosine monophosphate (cGMP) signal and protein kinase A activity in myocytes. Acute stimulation of myocytes with carvedilol promotes β1 adrenergic receptor (β1 AR)- and protein kinase G (PKG)-dependent inotropic cardiac contractility with minimal increases in calcium amplitude. Carvedilol acts as a biased ligand to promote β1 AR coupling to a Gi -PI3K-Akt-nitric oxide synthase 3 (NOS3) cascade and induces robust β1 AR-cGMP-PKG signal. Deletion of NOS3 selectively blocks carvedilol, but not isoproterenol-induced β1 AR-dependent cGMP signal and inotropic contractility. Moreover, therapy with carvedilol restores inotropic contractility and sensitizes cardiac adrenergic reserves in diabetic mice with minimal impact in calcium signal, as well as reduced cell apoptosis and hypertrophy in diabetic hearts. Conclusion: These observations present a novel β1 AR-NOS3 signalling pathway to promote cardiac inotropy in the heart, indicating that this signalling paradigm may be targeted in therapy of heart diseases with reduced ejection fraction.