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Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia
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Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia
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Journal Article
Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia
2016
Overview
Rac1 is a small GTPase and plays key roles in multiple cellular processes including the production of reactive oxygen species (ROS). However, whether Rac1 activation during myocardial ischaemia and reperfusion (I/R) contributes to arrhythmogenesis is not fully understood. We aimed to study the effects of Rac1 inhibition on store overload‐induced Ca2+ release (SOICR) and ventricular arrhythmia during myocardial I/R. Adult Rac1f/f and cardiac‐specific Rac1 knockdown (Rac1ckd) mice were subjected to myocardial I/R and their electrocardiograms (ECGs) were monitored for ventricular arrhythmia. Myocardial Rac1 activity was increased and ventricular arrhythmia was induced during I/R in Rac1f/f mice. Remarkably, I/R‐induced ventricular arrhythmia was significantly decreased in Rac1ckd compared to Rac1f/f mice. Furthermore, treatment with Rac1 inhibitor NSC23766 decreased I/R‐induced ventricular arrhythmia. Ca2+ imaging analysis showed that in response to a 6 mM external Ca2+ concentration challenge, SOICR was induced with characteristic spontaneous intracellular Ca2+ waves in Rac1f/f cardiomyocytes. Notably, SOICR was diminished by pharmacological and genetic inhibition of Rac1 in adult cardiomyocytes. Moreover, I/R‐induced ROS production and ryanodine receptor 2 (RyR2) oxidation were significantly inhibited in the myocardium of Rac1ckd mice. We conclude that Rac1 activation induces ventricular arrhythmia during myocardial I/R. Inhibition of Rac1 suppresses SOICR and protects against ventricular arrhythmia. Blockade of Rac1 activation may represent a new paradigm for the treatment of cardiac arrhythmia in ischaemic heart disease.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Arrhythmias, Cardiac - metabolism
/ Arrhythmias, Cardiac - pathology
/ Arrhythmias, Cardiac - prevention & control
/ Heart
/ Heart Ventricles - pathology
/ Ischemia
/ Myocytes, Cardiac - metabolism
/ Original
/ Proteins
/ Rac1
/ rac1 GTP-Binding Protein - antagonists & inhibitors
/ rac1 GTP-Binding Protein - metabolism
/ Ryanodine Receptor Calcium Release Channel - metabolism
