Abstract 10606: Plasticity of Surface Structures and Beta 2-adrenergic Receptor Localization in Failing Ventricular Cardiomyocytes During Recovery From Heart Failure
β1 and β2 adrenergic G-protein-coupled receptors (βARs) are important mediators of cardiac function regulating production of the second messenger 3’,5’-cyclic adenosine monophosphate (cAMP). However, they differ in their effect both in normal heart and in heart failure. Recently, using scanning ion conductance microscopy combined with FRET technique, we found that β2AR-induced cAMP signals are localized exclusively to the deep transverse tubules, whereas functional β1ARs are distributed across the entire cell surface of healthy cardiomyocytes. In a rat model of chronic heart failure, β2ARs redistributed from the transverse tubules to the cell crest, leading to diffuse receptor-mediated cAMP signaling. We showed that surface morphology and T-tubular structure are significantly disrupted in chronic heart failure cells, and that impacts on the redistribution of sarcolemmal β2AR and localized secondary messenger signaling. (PNAS, 2009,106:16854-9; Science,2010, 26:1653-7.) Here we used AAV9.SERCA2a gene therapy to rescue failing rat hearts, and measured z-groove index, T-tubule density and compartmentalized β2AR-mediated cAMP signals using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. Cardiomyocyte surface morphology, quantified by z-groove index and T-tubule density, was normalized in reverse remodeled hearts following SERCA2a gene therapy. Recovery of sarcolemmal microstructure correlated with functional β2AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated following local β2AR stimulation of crest membrane, as observed in failing cardiomyocytes. A subgroup of cardiomyocytes from rescued hearts showed partial topological recovery, with persistence of β2AR-stimulated cAMP responses at the crest membrane. Improvement of β2AR localization was associated with recovery of βAR-stimulated contractile responses in rescued cardiomyocytes. In summary, abnormalities of sarcolemmal structure in heart failure show plasticity with reappearance of z-grooves and T-tubules in reverse remodeled hearts, and recovery of surface topology is necessary for normalization of β2AR location and signaling responses.
- © 2011 by American Heart Association, Inc.