Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

Abstract

BackgroundOxidative stress–mediated Ca2+/calmodulin‐dependent protein kinase II (CaMKII) phosphorylation of cardiac ion channels has emerged as a critical contributor to arrhythmogenesis in cardiac pathology. However, the link between mitochondrial‐derived reactive oxygen species (mdROS) and increased CaMKII activity in the context of cardiac arrhythmias has not been fully elucidated and is difficult to establish experimentally.Methods and ResultsWe hypothesize that pathological mdROS can cause erratic action potentials through the oxidation‐dependent CaMKII activation pathway. We further propose that CaMKII‐dependent phosphorylation of sarcolemmal slow Na+ channels alone is sufficient to elicit early afterdepolarizations. To test the hypotheses, we expanded our well‐established guinea pig cardiomyocyte excitation‐contraction coupling, mitochondrial energetics, and ROS‐induced‐ROS‐release model by incorporating oxidative CaMKII activation and CaMKII‐dependent Na+ channel phosphorylation in silico. Simulations show that mdROS mediated‐CaMKII activation elicits early afterdepolarizations by augmenting the late Na+ currents, which can be suppressed by blocking L‐type Ca2+ channels or Na+/Ca2+ exchangers. Interestingly, we found that oxidative CaMKII activation–induced early afterdepolarizations are sustained even after mdROS has returned to its physiological levels. Moreover, mitochondrial‐targeting antioxidant treatment can suppress the early afterdepolarizations, but only if given in an appropriate time window. Incorporating concurrent mdROS‐induced ryanodine receptors activation further exacerbates the proarrhythmogenic effect of oxidative CaMKII activation.ConclusionsWe conclude that oxidative CaMKII activation–dependent Na channel phosphorylation is a critical pathway in mitochondria‐mediated cardiac arrhythmogenesis.

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

“…Moreover, the increased cytosolic Ca 2+ levels can lead to mitochondrial Ca 2+ overload, further increasing ROS production and ultimately resulting in cell death (Figure 2) (Gambardella et al, 2017). It has been shown that oxidative CaMKII activation leads to after depolarization's in isolated rabbit cardiomyocytes, caused by phosphorylation of L-type Ca 2+ (LTCC) and Na + channels (Yang et al, 2018). In addition, mitochondrial-targeted antioxidant treatment has shown to suppress early after depolarization's (EADs) in an in silico model of guinea pig cardiomyocytes (Yang et al, 2018).…”

“…It has been shown that oxidative CaMKII activation leads to after depolarization's in isolated rabbit cardiomyocytes, caused by phosphorylation of L-type Ca 2+ (LTCC) and Na + channels (Yang et al, 2018). In addition, mitochondrial-targeted antioxidant treatment has shown to suppress early after depolarization's (EADs) in an in silico model of guinea pig cardiomyocytes (Yang et al, 2018). Phosphorylation of Na V 1.5 delays the I Na recovery time after inactivation and enhances the persistent late Na + current (Wagner et al, 2006).…”

Pathological Responses of Cardiac Mitochondria to Burn Trauma

“…Growing evidence has further indicated the importance of mitochondrial Ca 2+ in arrhythmogenesis [ 140 ]. Mitochondrial ROS production induces RyR2 oxidation [ 141 ] and/or oxidative activation of Ca 2+ /calmodulin-dependent protein kinase II [ 142 ], leading to mitochondrial Ca 2+ overload that contributes strongly to arrhythmogenesis in cardiac pathology.…”

Mitochondrial Dysfunction-Associated Arrhythmogenic Substrates in Diabetes Mellitus

“…Xie et al (2009) have showed that H 2 O 2 perfusion-induced oxidative CaMKII activation leads to afterdepolarizations in isolated rabbit cardiomyocytes, likely via phosphorylation of Na + channels and LCCs. In a computational study, Yang R. et al (2018) reported that mdROS-mediated oxidative CaMKII activation induces EADs in guinea pig cardiomyocytes by enhancing the late component of Na + current. The proarrhythmic role of CaMKII oxidation in diabetic hearts has been demonstrated in a recent study showing that selective genetic blocking of CaMKII oxidation prevents the enhanced atrial fibrillation (AF) risk (Mesubi et al, 2017), which has been implicated to be associated with increased mortality in response to myocardial infraction (Luo et al, 2013).…”