Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure

Ying Wang; Meimi Zhao; Xianhui Liu; Bing Xu; Gopireddy R Reddy; Aleksandra Jovanovic; Qingtong Wang; Chaoqun Zhu; Heli Xu; Elizabeth F Bayne; Wenjing Xiang; Douglas G Tilley; Ying Ge; Christopher G Tate; Robert Feil; Joanna C Chiu; Donald M Bers; Yang K Xiang

doi:10.1016/j.jacbts.2024.03.007

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure

JACC Basic Transl Sci. 2024 May 29;9(8):982-1001. doi: 10.1016/j.jacbts.2024.03.007. eCollection 2024 Aug.

Authors

Ying Wang^{1

2}, Meimi Zhao¹, Xianhui Liu³, Bing Xu^{1

4}, Gopireddy R Reddy¹, Aleksandra Jovanovic¹, Qingtong Wang¹, Chaoqun Zhu¹, Heli Xu⁵, Elizabeth F Bayne⁶, Wenjing Xiang², Douglas G Tilley⁵, Ying Ge⁶, Christopher G Tate⁷, Robert Feil⁸, Joanna C Chiu³, Donald M Bers¹, Yang K Xiang^{1

4}

Affiliations

¹ Department of Pharmacology, University of California-Davis, Davis, California, USA.
² Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
³ Department of Entomology and Nematology, University of California-Davis, Davis, California, USA.
⁴ VA Northern California Health Care System, Mather, California, USA.
⁵ Department of Cardiovascular Sciences, Temple University, Philadelphia, Pennsylvania, USA.
⁶ Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁷ MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
⁸ Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.

Abstract

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local βAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different βAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by β₁AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca²⁺) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β₁AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β₁AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with β₁AR were observed. Stimulating β₁AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β₁AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca²⁺ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Keywords: contractility; heart failure; myofilament; myosin light chain; nitric oxide synthetase; protein kinase G; β1-adrenoceptor.