Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy

TY - JOUR

T1 - Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy

AU - Perera, Ruwan K

AU - Sprenger, Julia U

AU - Steinbrecher, Julia H

AU - Hübscher, Daniela

AU - Lehnart, Stephan E

AU - Abesser, Marco

AU - Schuh, Kai

AU - El-Armouche, Ali

AU - Nikolaev, Viacheslav O

N1 - © 2015 American Heart Association, Inc.

PY - 2015/4/10

Y1 - 2015/4/10

N2 - RATIONALE: Cyclic nucleotides are second messengers that regulate cardiomyocyte function through compartmentalized signaling in discrete subcellular microdomains. However, the role of different microdomains and their changes in cardiac disease are not well understood.OBJECTIVE: To directly visualize alterations in β-adrenergic receptor-associated cAMP and cGMP microdomain signaling in early cardiac disease.METHODS AND RESULTS: Unexpectedly, measurements of cell shortening revealed augmented β-adrenergic receptor-stimulated cardiomyocyte contractility by atrial natriuretic peptide/cGMP signaling in early cardiac hypertrophy after transverse aortic constriction, which was in sharp contrast to well-documented β-adrenergic and natriuretic peptide signaling desensitization during chronic disease. Real-time cAMP analysis in β1- and β2-adrenergic receptor-associated membrane microdomains using a novel membrane-targeted Förster resonance energy transfer-based biosensor transgenically expressed in mice revealed that this unexpected atrial natriuretic peptide effect is brought about by spatial redistribution of cGMP-sensitive phosphodiesterases 2 and 3 between both receptor compartments. Functionally, this led to a significant shift in cGMP/cAMP cross-talk and, in particular, to cGMP-driven augmentation of contractility in vitro and in vivo.CONCLUSIONS: Redistribution of cGMP-regulated phosphodiesterases and functional reorganization of receptor-associated microdomains occurs in early cardiac hypertrophy, affects cGMP-mediated contractility, and might represent a previously not recognized therapeutically relevant compensatory mechanism to sustain normal heart function.

AB - RATIONALE: Cyclic nucleotides are second messengers that regulate cardiomyocyte function through compartmentalized signaling in discrete subcellular microdomains. However, the role of different microdomains and their changes in cardiac disease are not well understood.OBJECTIVE: To directly visualize alterations in β-adrenergic receptor-associated cAMP and cGMP microdomain signaling in early cardiac disease.METHODS AND RESULTS: Unexpectedly, measurements of cell shortening revealed augmented β-adrenergic receptor-stimulated cardiomyocyte contractility by atrial natriuretic peptide/cGMP signaling in early cardiac hypertrophy after transverse aortic constriction, which was in sharp contrast to well-documented β-adrenergic and natriuretic peptide signaling desensitization during chronic disease. Real-time cAMP analysis in β1- and β2-adrenergic receptor-associated membrane microdomains using a novel membrane-targeted Förster resonance energy transfer-based biosensor transgenically expressed in mice revealed that this unexpected atrial natriuretic peptide effect is brought about by spatial redistribution of cGMP-sensitive phosphodiesterases 2 and 3 between both receptor compartments. Functionally, this led to a significant shift in cGMP/cAMP cross-talk and, in particular, to cGMP-driven augmentation of contractility in vitro and in vivo.CONCLUSIONS: Redistribution of cGMP-regulated phosphodiesterases and functional reorganization of receptor-associated microdomains occurs in early cardiac hypertrophy, affects cGMP-mediated contractility, and might represent a previously not recognized therapeutically relevant compensatory mechanism to sustain normal heart function.

KW - 3',5'-Cyclic-AMP Phosphodiesterases

KW - Adrenergic beta-Agonists

KW - Animals

KW - Atrial Natriuretic Factor

KW - Biosensing Techniques

KW - Cardiomegaly

KW - Cyclic GMP

KW - Cyclic Nucleotide Phosphodiesterases, Type 2

KW - Cyclic Nucleotide Phosphodiesterases, Type 3

KW - Disease Models, Animal

KW - Enzyme Activation

KW - Female

KW - Fluorescence Resonance Energy Transfer

KW - Guanine Nucleotide Exchange Factors

KW - Isoproterenol

KW - Membrane Microdomains

KW - Mice

KW - Mice, Transgenic

KW - Myocardial Contraction

KW - Myocytes, Cardiac

KW - Protein Transport

KW - Receptor Cross-Talk

KW - Receptors, Adrenergic, beta

KW - Receptors, Adrenergic, beta-1

KW - Receptors, Adrenergic, beta-2

KW - Second Messenger Systems

KW - Time Factors

U2 - 10.1161/CIRCRESAHA.116.306082

DO - 10.1161/CIRCRESAHA.116.306082

M3 - SCORING: Journal article

C2 - 25688144

VL - 116

SP - 1304

EP - 1311

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 8

ER -