Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: effects of genotype and sex

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is associated with mutations in the cardiac ryanodine receptor (RyR2). These result in stress-induced ventricular arrhythmic episodes, with clinical symptoms and prognosis reported more severe in male than female patients. Murine homozygoticRyR2-P2328S(RyR2(S/S)) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca(2+)leak and disrupted Ca(2+)homeostasis. In addition,RyR2(S/S)hearts show decreased myocardial action potential conduction velocities (CV), all features implicated in arrhythmic trigger and substrate. The present studies explored for independent and interacting effects ofRyR2(S/S)genotype and sex on expression levels of molecular determinants of Ca(2+)homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and Ca(V)1.2) and CV (Na(V)1.5, Connexin (Cx)-43, phosphorylated-Cx43, and TGF-beta 1) in mice. Expression levels of Ca(2+)homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca(2+)homeostasis. Furthermore, altered Na(V)1.5, phosphorylated Cx43, and TGF-beta 1 expression were not implicated in the development of slowed CV. By contrast, decreased Cx43 expression correlated with slowed CV, in female, but not male,RyR2(S/S)mice. The CV changes may reflect acute actions of the increased cytosolic Ca(2+)on Na(V)1.5 and Cx43 function.