Study of EPAC1 role in aging
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International audience. Introduction: Although the life expectancy has increased this has not been accompanied by healthier aging, creating thus, a social and economic burden. In this regard, one of the major causes of disability among older people is cardiovascular diseases, in particular, heart failure with preserved ejection fraction (HFpEF). The aging heart is characterized by the presence of fibrosis, hypertrophy, apoptosis, and senescence. The latter leads to cell cycle arrest, increased activity of Beta-galactosidase, DNA damage, and the secretion of pro-inflammatory molecules.In the last years, it has become a central aim to find a therapy that could target heart aging and senescence. Interestingly, It has been shown that an increase of cAMP in the aging heart aggravates age-related pathologies, but the players involved in such 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 remodelling leading to heart failure making this protein a potential target to modulate cardiac aging.Objective: This project aims to determine the potential role of EPAC1 in cardiac aging.Methods: In rat neonatal cardiomyocytes we tested EPAC1 participation in senescence activation. To this effect, we used EPAC's specific activator 8-CPT and inhibitor CE3F4 and evaluated Beta-galactosidase activity, and DNA damage. For in vivo studies we used 6 month-old (young) and 24 month-old (old) mice both WT and KO for EPAC1. To assess diastolic dysfunction, we performed cardiac echography before and after an acute injection of Isoproterenol. We also evaluated cross sectional area by immunostaining, and the presence of inflammation and senescence markers by qPCR. Finally, we used human samples of young, old patients and patients with HFpEF and measured the levels of expression of EPAC1 by qPCR.Results: In this work, we found that activating EPAC1 induces both beta-galactosidase activation and DNA damage and that both processes can be reversed by CE3F4. We also found that Doxorubicin-induced senescence is decreased by blocking EPAC1. In vivo, we determined that EPAC1 protein expression is increased in old mice. Also, we found that after Isoproterenol stress, isovolumic relaxation time (IVRT) is unchanged in old EPAC1 KO mice. In immunostaining analysis we found that cellular hypertrophy is decreased in Old KO mice compared to WT. At the molecular level, we found that senescence and inflammation markers are increased in the WT but not in the KO mice. Finally, mRNA expression of EPAC1 is increased in HFpEF patients compared to young subjects.Conclusion: EPAC1 is involved in the detrimental process of cardiac aging due to its role in increasing senescense, inflammation and cellular hypertrophy. These results highlight the importance of studying EPAC1 as a potential therapeutic target for cardiovascular diseases related to aging.
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