Triggered Ca²⁺-dependent mechanism of early age-related impairments in cardiac contractile function in male and female rats

Abstract

Age-related structural and functional changes in the heart are diagnosed earlier in males than in females. The mechanisms underlying sex differences in age-associated electrical instability and impaired myocardial contractility remain insufficiently studied. Aim: To investigate sex-specific age-related changes in the transcriptional activity of genes encoding key proteins maintaining electrical stability and myocardial contractility—CaV1.2, KV1 channels, IP3R and RyR2 receptors, and regulatory proteins SERCA2, phospholamban , calmodulin, and Epac2. Materials and Methods: The study was conducted on male and female Wistar rats aged 4 and 18 months. Using PCR analysis, gene expression of the aforementioned proteins was evaluated in the atria and left ventricle of young and aged rats. Results: In male rats, aging was associated with more pronounced disruptions in calcium-handling proteins compared to females. In aged males, significant upregulation of genes encoding voltage-gated CaV1.2 and KV1.1 channels, ryanodine RyR2 receptors, inositol trisphosphate IP3R1, IP3R2, IP3R3 receptors, and their regulators—calmodulin, Epac2, sarcoplasmic Ca²⁺-ATPase (SERCA2), and phospholamban—was observed in the left ventricle and atria. In females, age-related gene expression changes in the left ventricle were minimal, with only increased mRNA levels of Epac2 and CaM, and reduced RyR2 and IP3R3. Major deviations from young females were detected in the atria, particularly the right atrium: hyperexpression of KV1.1 and CaV1.2 channels, RyR2, IP3R1, IP3R3 receptors, and Epac2, CaM proteins. Both sexes showed marked reduction in KV1.6 channel mRNA levels. Conclusion: Age-related disruptions in cardiac rhythm and myocardial contractility are proposed to be triggered by altered transcriptional activity of genes regulating calcium homeostasis and electrical myocardial activity. These changes are more pronounced in males.