Sex differences in expression of calcium-handling proteins and beta-adrenergic receptors in rat heart ventricle

Human studies reveal sex differences in myocardial function as well as in the incidence and manifestation of heart disease. Myocellular Ca²⁺ cycling regulates normal contractile function; whereas cardiac dysfunction in heart failure has been associated with alterations in Ca²⁺-handling proteins. Beta-adrenergic receptor (β-AR) signaling regulates activity of several Ca²⁺-handling proteins and alterations in β-AR signaling are associated with heart disease. This study examines sex differences in expression of β₁-AR, β₂-AR, and Ca ²⁺-handling proteins including: L-type calcium channel (Ca _v1.2), ryanodine calcium-release channels (RyR), sarcoplasmic reticular Ca²⁺ ATPase (SERCA2), phospholamban (PLB) and Na ⁺-Ca²⁺ exchange protein (NCX) in healthy hearts from male and female Sprague-Dawley rats. Protein levels were examined using Western blot analysis. Abundance of mRNA was determined by real time RT-PCR normalized to abundance of GAPDH mRNA. Contraction parameters were measured in right ventricular papillary muscle in the presence and absence of isoproterenol. Results demonstrate that female ventricle has significantly higher levels of Ca_v1.2, RyR, and NCX protein compared to males. Messenger RNA abundance for RyR, and NCX protein was significantly higher in females whereas Ca_v1.2 mRNA was higher in males. No differences were detected in β-ARs, SERCA2 or PLB. Female right papillary muscle had a faster maximal rate of force development and decline (± dF/dt). There were no sex differences in response to isoproterenol. Results show significant sex differences in expression of key ventricular Ca²⁺-handling proteins that are associated with small functional differences in ± dF/dt. Further studies will determine whether differences in the abundance of these key proteins play a role in sex disparities in the incidence and manifestation of heart disease.