Xia Yi-Yuan, Shi Yi, Li Zheng, Li Hui, Wu Li-Da, Zhou Wen-Ying, Gu Yue, Ling Zhi-Yu, Zhang Jun-Xia, Chen Shao-Liang
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, Nanjing, China.
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, Nanjing, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
Biochem Biophys Res Commun. 2022 Dec 25;636(Pt 2):62-70. doi: 10.1016/j.bbrc.2022.10.109. Epub 2022 Nov 2.
Epicardial adipose tissue (EAT) is a metabolically active organ which generates inflammatory cytokines. Thickness of EAT is associated with onset and development of heart failure with preserved ejection fraction (HFpEF). However, it is still unclear the specific mechanisms and pharmacological targets on EAT induced inflammation in HFpEF. A two-hit protocol with western diet and N-nitrol-arginine methyl ester (L-NAME) was used to establish HFpEF mouse model. In HFpEF mice, inflammatory biomarkers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and von willebrand factor (vWF) elevated in myocardium compared to control. Inflammatory cell infiltration in myocardium was increased. In HFpEF mice, inflammasome-mediated pyroptosis pathway was activated in the EAT. Suppression of pyroptosis-related protein gasdermin D (GSDMD) in cultured EAT could lower cardiomyocyte inflammation and autophagy. Furthermore, spironolactone and rosuvastatin, the two-hit anti-inflammatory agents, reduced NLR family pyrin domain containing 3 (NLRP3)/GSDMD pyroptosis in EAT and autophagy in myocardium of HFpEF mouse. The combination treatment also enhanced exercise tolerance and appeased inflammatory injuries in HFpEF mice. CONCLUSION: Pyroptosis signaling is involved in EAT-myocardium axis in mouse model of HFpEF. Targeting adipocyte-derived inflammation in EAT bears potential to treatment HFpEF.
心外膜脂肪组织（EAT）是一个产生炎性细胞因子的代谢活跃器官。EAT的厚度与射血分数保留的心力衰竭（HFpEF）的发生和发展相关。然而，HFpEF中EAT诱导炎症的具体机制和药理学靶点仍不清楚。采用西式饮食和N-硝基-L-精氨酸甲酯（L-NAME）的双打击方案建立HFpEF小鼠模型。与对照组相比，HFpEF小鼠心肌中的炎性生物标志物，如肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和血管性血友病因子（vWF）升高。心肌中的炎性细胞浸润增加。在HFpEF小鼠中，EAT中炎性小体介导的细胞焦亡途径被激活。在培养的EAT中抑制细胞焦亡相关蛋白gasdermin D（GSDMD）可降低心肌细胞炎症和自噬。此外，螺内酯和瑞舒伐他汀这两种抗炎药物可减少HFpEF小鼠EAT中的NLR家族含pyrin结构域3（NLRP3）/GSDMD细胞焦亡以及心肌中的自噬。联合治疗还提高了HFpEF小鼠的运动耐力并减轻了炎性损伤。结论：细胞焦亡信号参与了HFpEF小鼠模型的EAT-心肌轴。针对EAT中脂肪细胞衍生的炎症进行靶向治疗具有治疗HFpEF的潜力。
