Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy
Standard
Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy. / Perera, Ruwan K; Sprenger, Julia U; Steinbrecher, Julia H; Hübscher, Daniela; Lehnart, Stephan E; Abesser, Marco; Schuh, Kai; El-Armouche, Ali; Nikolaev, Viacheslav O.
in: CIRC RES, Jahrgang 116, Nr. 8, 10.04.2015, S. 1304-11.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
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 -