Involvement of plasminogen activator inhibitor-1 in p300/p53-mediated age-related atrial fibrosis
Yingyu Lai,
Jintao He,
Xiaoyan Gao,
Dewei Peng,
Huishan Zhou,
Yuwen Xu,
Xueshan Luo,
Hui Yang,
Mengzhen Zhang,
Chunyu Deng,
Shulin Wu,
Yumei Xue,
Feng Zhou,
Fang Rao
Affiliations
Yingyu Lai
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Jintao He
School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
Xiaoyan Gao
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Dewei Peng
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Huishan Zhou
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Yuwen Xu
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Xueshan Luo
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Hui Yang
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Mengzhen Zhang
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Chunyu Deng
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Shulin Wu
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Yumei Xue
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Feng Zhou
Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
Fang Rao
Medical Research Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is also intimately involved in the fibrosis. Although PAI-1 may be involved in the occurrence of atrial fibrillation (AF) and thrombosis in the elderly, but whether it participated in aging-related atrial fibrosis and the detailed mechanism is still unclear. We compared the transcriptomics data of young (passage 4) versus senescent (passage 14) human atrial fibroblasts and found that PAI-1 was closely related to aging-related fibrosis. Aged mice and senescent human and mouse atrial fibroblasts underwent electrophysiological and biochemical studies. We found that p300, p53, and PAI-1 protein expressions were increased in the atrial tissue of aged mice and senescent human and mouse atrial fibroblasts. Curcumin or C646 (p300 inhibitor), or p300 knockdown inhibited the expression of PAI-1 contributing to reduced atrial fibroblasts senescence, atrial fibrosis, and the AF inducibility. Furthermore, p53 knockdown decreased the protein expression of PAI-1 and p21 in senescent human and mouse atrial fibroblasts. Our results suggest that p300/p53/PAI-1 signaling pathway participates in the mechanism of atrial fibrosis induced by aging, which provides new sights into the treatment of elderly AF.
