Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors

Abstract

Cardiomyocyte Na+ and Ca2+ mishandling, upregulated Ca2+/calmodulin-dependent kinase II (CaMKII), and increased reactive oxygen species (ROS) are characteristics of various heart diseases, including heart failure (HF), long QT (LQT) syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT). These changes may form a vicious cycle of positive feedback to promote cardiac dysfunction and arrhythmias. In HF rabbit cardiomyocytes investigated in this study, the inhibition of CaMKII, late Na+ current (INaL), and leaky ryanodine receptors (RyRs) all attenuated the prolongation and increased short-term variability (STV) of action potential duration (APD), but in age-matched controls these inhibitors had no or minimal effects. In control cardiomyocytes, we enhanced RyR leak (by low [caffeine] plus isoproterenol mimicking CPVT) which markedly increased STV and delayed afterdepolarizations (DADs). These proarrhythmic changes were significantly attenuated by both CaMKII inhibition and mitochondrial ROS scavenging, with a slight synergy with INaL inhibition. Inducing LQT by elevating INaL (by Anemone toxin II, ATX-II) caused markedly prolonged APD, increased STV, and early afterdepolarizations (EADs). Those proarrhythmic ATX-II effects were largely attenuated by mitochondrial ROS scavenging, and partially reduced by inhibition of CaMKII and pathological leaky RyRs using dantrolene. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) bearing LQT3 mutation SCN5A N406K, dantrolene significantly attenuated cell arrhythmias and APD prolongation. Targeting critical components of the Na+–Ca2+–CaMKII–ROS–INaL arrhythmogenic vicious cycle may exhibit important on-target and also trans-target effects (e.g., INaL and RyR inhibition can alter INaL-mediated LQT3 effects). Incorporating this vicious cycle into therapeutic strategies provides novel integrated insight for treating cardiac arrhythmias and diseases.

Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia

“…Abnormally high RyR2 channel activity has a central role in contractile deficiency and arrhythmogenesis underlying sudden cardiac death 3,4,49 and posttranslational modifications of the channel including PKA/CaMKII-mediated phosphorylation or oxidation are involved, as well as their interplay (ie, ROS-CaMKII-RyR2) at the cytosolic face of RyR2. 5,50 Here, we show a novel regulatory axis for RyR2 ROS modulation involving the luminal ROS sensor Ero1α and the luminal RyR2-binding protein ERp44. Our previous studies showed that β-adrenergic stimulation induces Ca 2+ -dependent VT/VF in 100% of ex vivo hearts from rats with pressure-overload induced hypertrophy.…”

Protein Kinase D1 Regulates Cardiac Hypertrophy, Potassium Channel Remodeling, and Arrhythmias in Heart Failure

“…Numerous other factors can contribute to arrhythmogenesis. Altered myocyte Ca 2+ handling and enhanced (CaMKII‐dependent) SR Ca 2+ leak are characteristic of HF, 61 which can increase APD alternans and afterdepolarizations. 47 , 48 , 49 , 50 Importantly, DADs were reduced post‐TAC in PKD1 cKO (Figure 8 ) in line with reduced cellular hypertrophy and larger I K1 density (Figures 4 and Figure S6 ).…”

Ventricular arrhythmia and sudden cardiac death in hypertrophic cardiomyopathy: From bench to bedside

“…To further explain the association between various sarcomere mutations and ion channel remodeling in experimental models, the potential mechanistic connections point to the critical calcium regulatory protein calcium calmodulin-dependent protein kinase II (CaMKII), which was proved to bridge the gap between gene variants and arrhythmogenic ion channelchanges ( 39 ). The autophosphorylation of CaMKII enhances its activity on downstream targets such as the phosphorylation of LTCC β-subunits, slowing down current inactivation and prolonging the entry of Ca2+ during systole ( 40 ). The phosphorylation of the Na+ channel (Nav1.5) changed the inactivation of INa, increasing INaL.…”

“…Increased INaL leads to APD prolongation, which increases the possibility of EAD and DAD, promoting calcium influx at the plateau phase, further aggravating calcium overload, and predisposing patients to arrhythmic diastolic dysfunction. INaL inhibitors shorten the APD and reduce calcium overload ( 20 , 40 ). It was also proved in cardiomyocytes isolated from septal myectomies of HCM patients as INaL inhibitor Ranolazine showed beneficial effects by lowering intracellular Ca2+ levels ( 24 ).…”