ER stress and calcium-dependent arrhythmias

Figures

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  FIGURE 1. Schematic depicting how ER stress and the UPR can exacerbate SR Ca2+ mishandling via in cardiovascular disease and contribute to Ca2+-dependent ventricular arrhythmogenesis. Diminished SR Ca2+ content due to decreased SERCA2a activity and/or increased RyR2 activity evokes ER stress and UPR that promotes ROS production mRNA and protein degradation and impair protein-protein interactions in Ca2+-handling complexes. This results in decreased repolarization reserve and slowing conduction due to reduction in K+ and Na+ ion channels in the plasmalemma. Additionally, further enhancement of RyR2 activity and reduction in SERCA2a activity promotes generation of pro-arrhythmic spontaneous SR Ca2+ waves. Image created with Biorender.com.

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  FIGURE 2. Schematic summarizing ER stress-associated modulation of RyR2 and SERCA2a occurring in diseased ventricular cardiomyocytes that contributes to arrhythmogenesis. Activation of ER stress and the UPR increases ERO1α expression/activity, promoting generation of ROS. ERO1α dissociates ERp44 from the RyR2 complex, increasing channel activity. Additionally, intra-SR oxidative stress promotes RyR2 oxidation at cytosolic face of the channel, exacerbating its hyperactivity. Putative oxidation of two intraluminal SERCA2a cysteines and Cysteine 674 at cytosolic face decreases the activity of transporter. SEPN1 serves as a redox sensor of SERCA2a, with low levels of luminal Ca2+ activating the protein as a reductase, and mitigating increased oxidation levels. Downregulation of HAX-1 in diseased hearts leads to less inhibition of the UPR by the protein, driving downstream SERCA2a oxidation and protein degradation. Image created with Biorender.com.