CNP regulates cardiac contractility and increases cGMP near both SERCA and TnI: difference from BNP visualized by targeted cGMP biosensors.

Autor:	Manfra O; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Calamera G; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Froese A; German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf and Institute of Experimental Cardiovascular Research, Hamburg, Germany., Arunthavarajah D; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Surdo NC; Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK., Meier S; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Melleby AO; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Aasrum M; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Aronsen JM; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway.; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway., Nikolaev VO; German Center for Cardiovascular Research, University Medical Center Hamburg-Eppendorf and Institute of Experimental Cardiovascular Research, Hamburg, Germany., Zaccolo M; Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, UK., Moltzau LR; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Levy FO; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway., Andressen KW; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, P.O. Box 1057 Blindern, 0316 Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2022 May 06; Vol. 118 (6), pp. 1506-1519.
DOI:	10.1093/cvr/cvab167
Abstrakt:	Aims: Guanylyl cyclase-B (GC-B; natriuretic peptide receptor-B, NPR-B) stimulation by C-type natriuretic peptide (CNP) increases cGMP and causes a lusitropic and negative inotropic response in adult myocardium. These effects are not mimicked by NPR-A (GC-A) stimulation by brain natriuretic peptide (BNP), despite similar cGMP increase. More refined methods are needed to better understand the mechanisms of the differential cGMP signalling and compartmentation. The aim of this work was to measure cGMP near proteins involved in regulating contractility to understand compartmentation of cGMP signalling in adult cardiomyocytes. Methods and Results: We constructed several fluorescence resonance energy transfer (FRET)-based biosensors for cGMP subcellularly targeted to phospholamban (PLB) and troponin I (TnI). CNP stimulation of adult rat cardiomyocytes increased cGMP near PLB and TnI, whereas BNP stimulation increased cGMP near PLB, but not TnI. The phosphodiesterases PDE2 and PDE3 constrained cGMP in both compartments. Local receptor stimulation aided by scanning ion conductance microscopy (SICM) combined with FRET revealed that CNP stimulation both in the t-tubules and on the cell crest increases cGMP similarly near both TnI and PLB. In ventricular strips, CNP stimulation, but not BNP, induced a lusitropic response, enhanced by inhibition of either PDE2 or PDE3, and a negative inotropic response. In cardiomyocytes from heart failure rats, CNP increased cGMP near PLB and TnI more pronounced than in cells from sham-operated animals. Conclusion: These targeted biosensors demonstrate that CNP, but not BNP, increases cGMP near TnI in addition to PLB, explaining how CNP, but not BNP, is able to induce lusitropic and negative inotropic responses. (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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