Abstract
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 homozygotic RyR2-P2328S (RyR2
) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca
leak and disrupted Ca
homeostasis. In addition, RyR2
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 of RyR2
genotype and sex on expression levels of molecular determinants of Ca
homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and Ca
1.2) and CV (Na
1.5, Connexin (Cx)-43, phosphorylated-Cx43, and TGF-β1) in mice. Expression levels of Ca
homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca
homeostasis. Furthermore, altered Na
1.5, phosphorylated Cx43, and TGF-β1 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
mice. The CV changes may reflect acute actions of the increased cytosolic Ca
on Na
1.5 and Cx43 function.