Sex Differences in Age-Related Changes in the Expression of Ryanodine Receptors RyR2 and Inositol-1,4,5-Trisphosphate Receptors IP<sub>3</sub>R1,2,3 and of Their Modulators СаM and Epac in Rat Aorta and Myocardium
The study was aimed at the assessment of age-related changes in the transcriptional activity of genes involved in the regulation of Ca<sup>2+</sup> signaling, specifically of the genes of IP<sub>3</sub>R and RyR and of their activity modulators CaM and Epac, in the vessels and myocardium of rats of both sexes. Expression was evaluated by the content of the mRNA of the studied protein related to the content of β-actin mRNA. It was shown that upon aging, unidirectional changes in the expression of genes encoding IP<sub>3</sub>Rs and RyR2 develop in the aorta of rats of both sexes, as well as various, sex-specific changes in the expression of genes of proteins CaM and Epac that modulate the activity of IP<sub>3</sub>R and RyR. In the vessels of old rats (24 months) of both sexes, relative levels of mRNA for IP<sub>3</sub>R of types 2 and 3 were reduced but remained unchanged for IP<sub>3</sub>R1 and significantly increased for RyR2 as compared with these indicators in young rats (4 months). In the aorta of old females, the relative mRNA content was reduced for CaM and Epac1 but remained unchanged for Epac2; in males, on the contrary, the expression of Epac1 and Epac2 was increased by 67% and 50%, respectively, as compared with corresponding parameters in young rats (4 months), but was not changed for CaM, which indicates gender differences in the violation of the subtle mechanisms of modulation of RyR2 and IP<sub>3</sub>Rs activity in blood vessels. Significant changes were revealed in the myocardium of old rats. In older males, an elevated expression was demonstrated for RyR2, IP<sub>3</sub>R1,2,3 in the left ventricle, for RyR2 and IP<sub>3</sub>R1 in the left atrium, and for RyR2 and IP<sub>3</sub>R3 in the right atrium. In contrast to males, in the left ventricle of females the mRNA content for RyR2 and IP<sub>3</sub>R1,2,3 was significantly lower than in young animals. In old females, the right atrium exhibited high expression levels of IP<sub>3</sub>R1 and IP<sub>3</sub>R3, and in the left atrium the expression level of IP<sub>3</sub>R3 was increased. In all parts of the heart of females, the expression of IP<sub>3</sub>R2 was unchanged. In the myocardium of old rats of both sexes, the expression of proteins CaM and Epac2 increased significantly. The revealed age-related differences in the transcriptional activity of genes involved in the regulation of intracellular Ca<sup>2+</sup> signaling at the level of IP<sub>3</sub>Rs and RyR2-mediated mechanisms suggest that with increasing life expectancy in males, the likelihood of developing myocardial hypertrophy and heart rhythm disturbance is significantly higher than in females.