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Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: effects of genotype and sex
Author(s) -
Saadeh Khalil,
Achercouk Zakaria,
Fazmin Ibrahim T.,
Nantha Kumar Nakulan,
Salvage Samantha C.,
Edling Charlotte E.,
Huang Christopher L.H.,
Jeevaratnam Kamalan
Publication year - 2020
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14426
Subject(s) - ryanodine receptor 2 , catecholaminergic polymorphic ventricular tachycardia , ryanodine receptor , medicine , homeostasis , endocrinology , biology , chemistry , receptor
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 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 of RyR2 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‐β1) 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‐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 Ca 2+ on Na V 1.5 and Cx43 function.