衰老
心房颤动
医学
内科学
内分泌学
心脏病学
纤维化
心肌梗塞
中庭(建筑)
病理
作者
Mehrzad Mehdizadeh,Patrice Naud,Issam Abu-Taha,Roddy Hiram,Feng Xiong,Jiening Xiao,Arnela Saljic,Markus Kamler,Nhung Vuong-Robillard,Éric Thorin,Gerardo Ferbeyre,Jean‐Claude Tardif,Martin G. Sirois,Jean François Tanguay,Dobromir Dobrev,Stanley Nattel
出处
期刊:Cardiovascular Research
[Oxford University Press]
日期:2024-01-05
被引量:1
摘要
Abstract Aims Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to: 1) Evaluate AF-susceptibility and senescence-marker expression in rat models of aging and myocardial infarction (MI); 2) Study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI-rats; 3) Assess senescence markers in human atrial tissue as a function of age and the presence of AF. Methods and Results AF-susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital-PCR or RT-qPCR (mRNA). A previously-validated senolytic combination, dasatinib and quercetin (D + Q), (or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment-assignment. Burst pacing-induced AF was seen in 100% of aged rats, 87.5% of young MI-rats and 10% of young-control rats (P≤0.001 vs. each). Conduction velocity was slower in aged (both left atrium, LA and right atrium, RA) and young-MI (LA) rats versus young-control rats (P≤0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young-MI (LA) versus young-control rats (P < 0.05 for each). Senolytic therapy reduced AF-inducibility in MI-rats (from 8/9 rats, 89% in MI-vehicle, to 0/9 rats, 0% in MI-D + Q, P < 0.001) and attenuated LA-fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence-markers were upregulated in older (≥ 70 years) and longstanding-AF patients versus individuals ≤ 60 and sinus-rhythm controls respectively. Conclusions Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.
科研通智能强力驱动
Strongly Powered by AbleSci AI