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 homozygotic RyR2-P2328S (RyR2^S/S ) hearts replicate the proarrhythmic CPVT phenotype of abnormal sarcoplasmic reticular Ca²⁺ leak and disrupted Ca²⁺ 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 of RyR2^S/S genotype and sex on expression levels of molecular determinants of Ca²⁺ homeostasis (CASQ2, FKBP12, SERCA2a, NCX1, and Ca_V 1.2) and CV (Na_V 1.5, Connexin (Cx)-43, phosphorylated-Cx43, and TGF-β1) in mice. Expression levels of Ca²⁺ homeostasis proteins were not altered, hence implicating abnormal RyR2 function alone in disrupted cytosolic Ca²⁺ homeostasis. Furthermore, altered Na_V 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^S/S mice. The CV changes may reflect acute actions of the increased cytosolic Ca²⁺ on Na_V 1.5 and Cx43 function.

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