Microdomain Switch of cGMP-Regulated Phosphodiesterases Leads to ANP-Induced Augmentation of β-Adrenoceptor-Stimulated Contractility in Early Cardiac Hypertrophy
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 (β-AR)-associated 3',5'-cyclic adenosine (cAMP) and guanosine (cGMP) microdomain signaling in early cardiac disease.
Methods and Results: Unexpectedly, measurements of cell shortening revealed augmented βAR-stimulated cardiomyocyte contractility by atrial natriuretic peptide (ANP)/cGMP signaling in early in cardiac hypertrophy following 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-AR-associated membrane microdomains using a novel membrane-targeted Förster resonance energy transfer-based biosensor transgenically expressed in mice revealed that this unexpected ANP 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.
- cardiac dysfunction
- cardiomyocyte hypertrophy
- cyclic nucleotide
- adrenergic receptor
- phosphodiesterase inhibitor
- Received January 19, 2015.
- Revision received February 5, 2015.
- Accepted February 16, 2015.