Renal denervation attenuates cardiac dysfunction in HFpEF by inhibiting the ATP-P2X7-NLRP3 inflammasome axis

作者：Zhuqing Li, Xiaoqiang Sun, Yanxin Wang, Feng Zhang, Li Wang, Chunbo Ai, Xu Zhang, Xuemei Yin, Chunlei Liu, Chao Li, Chengzhi Lu · 发表于：Basic Research in Cardiology · 年份：2025 · DOI：10.1007/s00395-025-01138-5 · 被引用次数：8 · 研究领域：Pulmonary Hypertension Research and Treatments、Cardiovascular Issues in Pregnancy、Congenital Heart Disease Studies

Heart failure with preserved ejection fraction (HFpEF) arises from intersecting comorbidities involving inflammation, metabolic stress, and sympathetic nervous system (SNS) activation. To mirror this complexity, we established a clinically oriented 3-hit mouse model combining advanced age, a high-fat diet, and chronic NOS inhibition with NG-Nitro-L-arginine methyl ester (L-NAME). We tested whether renal denervation (RDN) mitigates HFpEF by blunting SNS outflow and the ATP-P2X7-NLRP3 inflammasome axis, and in parallel probed the contribution of this pathway using pharmacologic and cellular approaches. 3-hit mice developed preserved ejection fraction with diastolic dysfunction, cardiomyocyte hypertrophy, interstitial fibrosis, impaired exercise capacity, and elevated inflammatory cytokines, accompanied by increased myocardial ATP, activation of P2X7/NLRP3 signaling, oxidative stress, and pyroptosis.RDN lowered systemic and myocardial norepinephrine, suppressed P2X7-NLRP3 inflammasome activation, reduced fibrosis and cardiomyocyte cross-sectional area, improved E/e' and exercise capacity, and reduced oxidative stress and myocardial injury. In pharmacological intervention experiments, selective blockade with the P2X7 antagonist A438079 or the NLRP3 inhibitor MCC950 improved diastolic function and exercise capacity and attenuated myocardial fibrosis and cardiomyocyte hypertrophy. Complementary mechanistic studies in cardiomyocytes (H9c2 and primary neonatal rat cardiomyocytes) sho...