Role of exchange protein directly activated by cAMP in cardiac aging

The aging of the heart is characterized by the presence of fibrosis, hypertrophy, inflammation, apoptosis, and senescence. It has been shown that an increase of cAMP in the aging heart aggravates age-related pathologies, but the players involved in this process have not been determined yet. In this sense, cAMP exerts its function through different effectors among which the Exchange protein directly activated by cAMP 1 (EPAC1) is involved in cardiac remodeling leading to heart failure making this protein a potential target to modulate cardiac aging. This project aims to determine the potential role of EPAC1 in cardiac aging and its possible mechanism of action. In rat neonatal cardiomyocytes we used EPAC's specific activator 8-CPT and inhibitor CE3F4 and evaluated Beta-galactosidase activity and DNA damage to determine senescence activation. For in vivo studies we used 6 month-old and 24 month-old WT or KO EPAC1 mice. To analyse diastolic dysfunction, we performed cardiac echography before and after an acute injection of Isoproterenol. We also evaluated cardiomyocyte cross-sectional areas by immunostaining and the presence of inflammation and senescence markers by qPCR. Finally, we used human samples of young, old patients and HFpEF patients and measured the levels of expression of EPAC1 by qPCR. We found that activating EPAC1 induced both beta-galactosidase activation and DNA damage and that both processes could be reversed by CE3F4. We also found that Doxorubicin-induced senescence was decreased by blocking EPAC1 activation. In vivo, we showed that EPAC1 protein expression was increased in old mice. In addition, we found that after Isoproterenol stress, isovolumic relaxation time (IVRT) was unchanged in old EPAC1 KO mice compared to WT. Immunostaining analysis demonstrated that cardiomyocyte hypertrophy was decreased in Old KO mice compared to WT. Interestingly, we found that senescence and inflammation markers were increased in the WT but not in the EPAC1 KO mice. Finally, mRNA expression of EPAC1 was upregulated in HFpEF patients compared to young subjects. Our findings show that EPAC1 promotes the detrimental process of cardiac aging by increasing senescence, inflammation, and cellular hypertrophy highlighting its potential as a therapeutic target for cardiovascular diseases related to aging.