Acetyltransferase p300 regulates atrial fibroblast senescence and age-related atrial fibrosis through p53/Smad3 axis.
Xiao-Yan GaoYing-Yu LaiXue-Shan LuoDe-Wei PengQiao-Qiao LiHui-Shan ZhouYu-Mei XueHui-Ming GuoJun-Fei ZhaoHui YangSu-Juan KuangZhao-Yu WangMeng-Zhen ZhangChun-Yu DengShu-Lin WuFang RaoPublished in: Aging cell (2022)
Atrial fibrosis induced by aging is one of the main causes of atrial fibrillation (AF), but the potential molecular mechanism is not clear. Acetyltransferase p300 participates in the cellular senescence and fibrosis, which might be involved in the age-related atrial fibrosis. Four microarray datasets generated from atrial tissue of AF patients and sinus rhythm (SR) controls were analyzed to find the possible relationship of p300 (EP300) with senescence and fibrosis. And then, biochemical assays and in vivo electrophysiological examination were performed on older AF patients, aging mice, and senescent atrial fibroblasts. The results showed that (1) the left atrial tissues of older AF patients, aging mouse, and senescence human atrial fibroblasts had more severe atrial fibrosis and higher protein expression levels of p300, p53/acetylated p53 (ac-p53)/p21, Smad3/p-Smads, and fibrosis-related factors. (2) p300 inhibitor curcumin and p300 knockdown treated aging mouse and senescence human atrial fibroblasts reduced the senescence ratio of atrial fibroblasts, ameliorated the atrial fibrosis, and decreased the AF inducibility. In contrast, over-expression of p300 can lead to the senescence of atrial fibroblasts and atrial fibrosis. (3) p53 knockdown decreased the expression of aging and fibrosis-related proteins. (4) Co-immunoprecipitation and immunofluorescence showed that p53 forms a complex with smad3 and directly regulates the expression of smad3 in atrial fibroblasts. Our findings suggest that the mechanism of atrial fibrosis induced by aging is, at least, partially dependent on the regulation of p300, which provides new sights into the AF treatment, especially for the elderly.
Keyphrases
- atrial fibrillation
- left atrial
- catheter ablation
- oral anticoagulants
- endothelial cells
- left atrial appendage
- direct oral anticoagulants
- heart failure
- percutaneous coronary intervention
- dna damage
- newly diagnosed
- end stage renal disease
- poor prognosis
- mitral valve
- prognostic factors
- transforming growth factor
- epithelial mesenchymal transition
- chronic kidney disease
- stress induced
- gene expression
- computed tomography
- type diabetes
- oxidative stress
- venous thromboembolism
- early onset
- risk assessment
- acute coronary syndrome
- long non coding rna
- peritoneal dialysis
- heart rate
- binding protein
- insulin resistance
- rna seq
- patient reported
- signaling pathway
- replacement therapy
- wound healing