Panigrahy Dipak, Kelly Abigail G, Quinlivan Katherine M, Wang Weicang, Yang Jun, Hwang Sung Hee, Gillespie Michael, Howard Isabella V, Bueno-Beti Carlos, Asimaki Angeliki, Penna Vinay, Lavine Kory, Edin Matthew L, Zeldin Darryl C, Hammock Bruce D, Saffitz Jeffrey E
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Department of Entomology and Nematology and UC-Davis Comprehensive Cancer Center, University of California, Davis, Calfornia, USA.
JACC Basic Transl Sci. 2025 Mar;10(3):367-380. doi: 10.1016/j.jacbts.2024.12.010. Epub 2025 Feb 5.
We analyzed the role of pro- and anti-inflammatory eicosanoids in the pathogenesis of arrhythmogenic cardiomyopathy (ACM). Lipidomics revealed reduced levels of anti-inflammatory oxylipins in plasma and increased levels of pro-inflammatory eicosanoids in hearts of Dsg2 mice, a preclinical model of ACM. Disease features were reversed in vitro in rat ventricular myocytes expressing mutant JUP by the anti-inflammatory epoxyeicosatrienoic acid 14-15-EET, whereas 14,15-EEZE, which antagonizes the 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that converts anti-inflammatory EETs into polar, less active diols, prevented progression of myocardial injury in Dsg2 mice and promoted recovery of contractile function. This was associated with reduced myocardial expression of genes involved in innate immune signaling and fewer injurious macrophages expressing CCR2. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM. Inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.
我们分析了促炎和抗炎类二十烷酸在致心律失常性心肌病（ACM）发病机制中的作用。脂质组学研究显示，在ACM临床前模型Dsg2小鼠的血浆中，抗炎氧化脂质水平降低，而心脏中促炎类二十烷酸水平升高。在体外，表达突变型JUP的大鼠心室肌细胞中，抗炎环氧二十碳三烯酸14-15-EET可逆转疾病特征，而拮抗14,15-EET受体的14,15-EEZE则增强了桥粒蛋白斑联蛋白的核内积累。抑制可溶性环氧化物水解酶（sEH）（一种将抗炎EETs转化为极性更强、活性更低的二醇的酶）可防止Dsg2小鼠心肌损伤进展，并促进收缩功能恢复。这与参与固有免疫信号传导的基因在心肌中的表达减少以及表达CCR2的有害巨噬细胞数量减少有关。这些结果表明，促炎类二十烷酸参与了ACM的发病机制。抑制sEH可能是一种针对ACM患者的有效、基于机制的治疗方法。
