title: Inhibition of Rac1 reduces store overload-induced calcium release and protects against ventricular arrhythmia.
abstract: 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 Ca(2+) release (SOICR) and ventricular arrhythmia during myocardial I/R. Adult Rac1(f/f) and cardiac-specific Rac1 knockdown (Rac1(ckd) ) 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 Rac1(f/f) mice. Remarkably, I/R-induced ventricular arrhythmia was significantly decreased in Rac1(ckd) compared to Rac1(f/f) mice. Furthermore, treatment with Rac1 inhibitor NSC23766 decreased I/R-induced ventricular arrhythmia. Ca(2+) imaging analysis showed that in response to a 6 mM external Ca(2+) concentration challenge, SOICR was induced with characteristic spontaneous intracellular Ca(2+) waves in Rac1(f/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 Rac1(ckd) 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.
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.|Nantong University Medical School, Nantong, China.
authors.forename: Le
authors.initials: L
authors.lastname: Gui
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.|Metabolic Syndrome Research Center, Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sims
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.|Lawson Health Research Institute, London, ON, Canada.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism*; D004562:Electrocardiography; D055785:Gene Knockdown Techniques; D006339:Heart Rate; D006352:Heart Ventricles / Q000473:pathology*; D008810:Mice, Inbred C57BL; D015425:Myocardial Reperfusion; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D013481:Superoxides; D020830:rac1 GTP-Binding Protein; D002118:Calcium
keywords: Rac1; arrhythmia; ischaemia and reperfusion; reactive oxygen species; store overload-induced calcium release