Plasticity of Surface Structures and β ₂ -Adrenergic Receptor Localization in Failing Ventricular Cardiomyocytes During Recovery From Heart Failure

Abstract

Background-Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal ␤ 2 -adrenergic receptors (␤ 2 AR) and localized secondary messenger signaling. Plasticity of these changes in the reverse remodeled failing ventricle is unknown. We used AAV9.SERCA2a gene therapy to rescue failing rat hearts and measured z-groove index, T-tubule density, and compartmentalized ␤ 2 AR-mediated cAMP signals, using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. Methods and Results-Cardiomyocyte surface morphology, quantified by z-groove index and T-tubule density, was normalized in reverse-remodeled hearts after SERCA2a gene therapy. Recovery of sarcolemmal microstructure correlated with functional ␤ 2 AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated after local ␤ 2 AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of ␤ 2 AR localization was associated with recovery of ␤AR-stimulated contractile responses in rescued cardiomyocytes. Retubulation was associated with reduced spatial heterogeneity of electrically stimulated calcium transients and recovery of myocardial BIN-1 and TCAP protein expression but not junctophilin-2. Conclusions-In summary, abnormalities of sarcolemmal structure in heart failure show plasticity with reappearance of z-grooves and T-tubules in reverse-remodeled hearts. Recovery of surface topology is necessary for normalization of ␤ 2 AR location and signaling responses. (Circ Heart Fail. 2012;5:357-365.)

Alpha-linolenic acid protects against cardiac injury and remodelling induced by beta-adrenergic overstimulation

“…Unlike these receptors, β 2 ARs can be confined into the caveolae, where they are coupled with G i protein, thus impairing cAMP production and activating a pro-survival pathway 33,[35][36][37] . Chronic βAR over-stimulation also induces the downregulation of caveolin-3 38 , the structural component of caveolae, allowing β 2 AR to move out of caveolae where they mediate the same effects of β 1 AR 33,35,39 .…”

Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health

“…This protective ionic diffusion barrier becomes even more significant during fast pacing states where restricted diffusion can effectively limit a quick depletion of extracellular calcium ions, preventing loss of transmembrane ionic flux. When cBIN1 is reduced as occurs in HF Lyon et al, 2012;Caldwell et al, 2014), not only channel localization to dyads is impaired, but also removal of the diffusion barrier can deplete extracellular ions, further diminishing LTCC current and impairing CICR (Figure 2, bottom panel).…”

“…with recovery of heart function (Lyon et al, 2012). Whether JPH2 can facilitate cBIN1-induced LTCC-RyR dyad formation is an interesting topic.…”

“…Later, a decrease in BIN1 transcription was identified in acquired human HF and multiple animal models of HF (Lyon et al, 2012;Caldwell et al, 2014), which recovers during functional recovery (Lyon et al, 2012). In failing cardiomyocytes, decreased BIN1 level impairs LTCC trafficking Lyon et al, 2012;Caldwell et al, 2014), diminishing calcium transients. In zebrafish, knockdown of Bin1 induces significant contractile dysfunction and cardiomyopathy .…”

“…As a result, functional LTCC-RyR couplons form at these cBIN1-microdomains, controlling CICR and E-C coupling. Furthermore, BIN1 is transcriptionally reduced in failing hearts Lyon et al, 2012), diminishing calcium transients and impairing cardiac contractility. Here we will review the most recent understanding of how BIN1 is coordinated to regulate the cardiac dyad system and its potential usage for HF prediction and therapy development.…”