Li Zhuqing, Sun Xiaoqiang, Wang Yanxin, Zhang Feng, Wang Li, Ai Chunbo, Zhang Xu, Yin Xuemei, Liu Chunlei, Li Chao, Lu Chengzhi
Department of Cardiology, Tianjin First Central Hospital, Tianjin, 300192, China.
Department of Physiology and Biomedical Engineering, Mayo Clinic, Scottsdale, AZ, 85259, USA.
Basic Res Cardiol. 2025 Sep 16. doi: 10.1007/s00395-025-01138-5.
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) showed that ATP induced mitochondrial ROS accumulation, inflammasome activation, cytokine release, and cell injury, which were partially reversed by P2X7 knockdown or pharmacological antagonism. Together, these data validate a multi-hit HFpEF model and implicate an SNS-driven ATP-P2X7-NLRP3 axis as a potential therapeutic target. Both RDN and selective pathway inhibition improved diastolic function and attenuated ventricular remodeling, and inform future therapeutic strategies for HFpEF characterized by heightened sympathetic tone.
射血分数保留的心力衰竭（HFpEF）源于涉及炎症、代谢应激和交感神经系统（SNS）激活的交叉合并症。为反映这种复杂性，我们建立了一种以临床为导向的三打击小鼠模型，该模型结合了老龄、高脂饮食以及用NG-硝基-L-精氨酸甲酯（L-NAME）进行慢性一氧化氮合酶抑制。我们测试了肾去神经支配（RDN）是否通过减弱SNS流出以及ATP-P2X7-NLRP3炎性小体轴来减轻HFpEF，并同时使用药理学和细胞方法探究该途径的作用。三打击小鼠出现了射血分数保留伴舒张功能障碍、心肌细胞肥大、间质纤维化、运动能力受损以及炎性细胞因子升高，同时伴有心肌ATP增加、P2X7/NLRP3信号激活、氧化应激和细胞焦亡。RDN降低了全身和心肌去甲肾上腺素水平，抑制了P2X7-NLRP3炎性小体激活，减少了纤维化和心肌细胞横截面积，改善了E/e'和运动能力，并降低了氧化应激和心肌损伤。在药理学干预实验中，用P2X7拮抗剂A438079或NLRP3抑制剂MCC950进行选择性阻断可改善舒张功能和运动能力，并减轻心肌纤维化和心肌细胞肥大。在心肌细胞（H9c2和原代新生大鼠心肌细胞）中进行的补充机制研究表明，ATP诱导线粒体ROS积累、炎性小体激活、细胞因子释放和细胞损伤，而P2X7基因敲低或药理学拮抗可部分逆转这些情况。总之，这些数据验证了一种多打击HFpEF模型，并表明SNS驱动的ATP-P2X7-NLRP3轴是一个潜在的治疗靶点。RDN和选择性途径抑制均改善了舒张功能并减轻了心室重塑，为以交感神经张力增强为特征的HFpEF的未来治疗策略提供了依据。
