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

Autor: Wang Y; Department of Pharmacology, University of California-Davis, Davis, California, USA.; Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China., Zhao M; Department of Pharmacology, University of California-Davis, Davis, California, USA., Liu X; Department of Entomology and Nematology, University of California-Davis, Davis, California, USA., Xu B; Department of Pharmacology, University of California-Davis, Davis, California, USA.; VA Northern California Health Care System, Mather, California, USA., Reddy GR; Department of Pharmacology, University of California-Davis, Davis, California, USA., Jovanovic A; Department of Pharmacology, University of California-Davis, Davis, California, USA., Wang Q; Department of Pharmacology, University of California-Davis, Davis, California, USA., Zhu C; Department of Pharmacology, University of California-Davis, Davis, California, USA., Xu H; Department of Cardiovascular Sciences, Temple University, Philadelphia, Pennsylvania, USA., Bayne EF; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Xiang W; Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China., Tilley DG; Department of Cardiovascular Sciences, Temple University, Philadelphia, Pennsylvania, USA., Ge Y; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Tate CG; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom., Feil R; Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany., Chiu JC; Department of Entomology and Nematology, University of California-Davis, Davis, California, USA., Bers DM; Department of Pharmacology, University of California-Davis, Davis, California, USA., Xiang YK; Department of Pharmacology, University of California-Davis, Davis, California, USA.; VA Northern California Health Care System, Mather, California, USA.
Jazyk: angličtina
Zdroj: JACC. Basic to translational science [JACC Basic Transl Sci] 2024 May 29; Vol. 9 (8), pp. 982-1001. Date of Electronic Publication: 2024 May 29 (Print Publication: 2024).
DOI: 10.1016/j.jacbts.2024.03.007
Abstrakt: 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 β 1 AR 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 (Ca 2+ ) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced β 1 AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the β 1 AR-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 β 1 AR were observed. Stimulating β 1 AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament β 1 AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca 2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.
Competing Interests: This work was supported by National Institutes of Health grants R01-HL147263 and HL162825, VA Merit grants IK6BX005753 and BX005100 (to Dr Xiang). Drs Wang and Zhu are recipients of American Heart Association postdoctoral fellowship. Dr Xiang is an established American Heart Association investigator. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2024 The Authors.)
Databáze: MEDLINE
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