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

• Published in: Circulation research 2015-04, Vol.116 (8), p.1304-1311
• Main Authors: Perera, Ruwan K, Sprenger, Julia U, Steinbrecher, Julia H, Hübscher, Daniela, Lehnart, Stephan E, Abesser, Marco, Schuh, Kai, El-Armouche, Ali, Nikolaev, Viacheslav O
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Adrenergic beta-Agonists - pharmacology; Animals; Atrial Natriuretic Factor - pharmacology; Biosensing Techniques; Cardiomegaly - enzymology; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cyclic GMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism; Disease Models, Animal; Enzyme Activation; Female; Fluorescence Resonance Energy Transfer; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Isoproterenol - pharmacology; Membrane Microdomains - drug effects; Membrane Microdomains - enzymology; Mice; Mice, Transgenic; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - pathology; Protein Transport; Receptor Cross-Talk - drug effects; Receptors, Adrenergic, beta - drug effects; Receptors, Adrenergic, beta - metabolism; Receptors, Adrenergic, beta-1 - drug effects; Receptors, Adrenergic, beta-1 - metabolism; Receptors, Adrenergic, beta-2 - drug effects; Receptors, Adrenergic, beta-2 - metabolism; Second Messenger Systems - drug effects; Time Factors
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.306082

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. To directly visualize alterations in β-adrenergic receptor-associated cAMP and cGMP microdomain signaling in early cardiac disease. 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. 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.