p300/Ahnak1 promotes the depression of ICa,L of atrial myocytes induced by aging

Atrial electrical remodeling induced by aging, characterized by decreased L-type calcium channel current (ICa,L) and shortened action potential duration (APD), contributes to the onset of atrial fibrillation (AF). Our previous study revealed that acetyltransferase p300 contributed to the aging-related atrial fibrosis. However, the role of p300 in aging-related atrial electrical remodeling is still unknown. In the present study, biochemical assays, whole-cell patch-clamp, and in vivo electrophysiological examination were performed on atrial tissues and atrial myocytes isolated from aged mice, and senescent atrium-derived cells (HL-1 cells). The results showed that: 1) Increased protein levels of p300, p53, p21 and p16, decreased Cav1.2/ICa,L, and shortened APD were found in the atrial tissues and atrial myocytes from aged mice, as well as senescent HL-1 cells. 2) In aged mice and senescent HL-1 cells, p300 knockdown and p300 inhibitor curcumin reduced the aging degree of atrial tissues, ameliorated the atrial electrical remodeling and decreased the inducibility of AF. 3) The expression of Ahnak1 and the association of Ahnak1 and Cavβ2 were increased in aged mice and senescent HL-1 cells, which could be reversed by p300 inhibition. Moreover, Ahnak1 directly regulated the expression of p21 and p16 in HL-1 cells. 4) Stability and conformational analyses indicated that the direct interaction between Ahnak1 and Cavβ2 is strong and stable. Our findings demonstrate that p300 contributes to atrial electrical remodeling induced by aging through regulation of the Ahnak1/Cavβ2 and Ahnak1/p21/p16 pathway, representing a potential pathogenic mechanism in AF.