Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia

• 成果类型: Article
• 署名作者: Kumowski, Nina; Pabel, Steffen; Grune, Jana; Momin, Noor; Ninh, Van K.; Stengel, Laura; Mentkowski, Kyle I.; Iwamoto, Yoshiko; Zheng, Yi; Lee, I-Hsiu; Matthias, Jessica; Wirth, Jan O.; Pulous, Fadi E.; Seung, Hana; Paccalet, Alexandre; Muse, Charlotte G.; Ting, Kenneth K. Y.; Delgado, Paul; Lewis, Andrew J. M.; Kaushal, Vaishali; Kreso, Antonia; Brown, Dennis; Hayat, Sikander; Kramann, Rafael; Swirski, Filip K.; Naxerova, Kamila; Propheter, Daniel C.; Hooper, Lora V.; Moskowitz, Michael A.; King, Kevin R.; Rosenthal, Nadia; Hulsmans, Maarten; Nahrendorf, Matthias
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Regensburg; University of California System; University of California San Diego; Kerckhoff Clinic; University of Oxford; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; RWTH Aachen University; Erasmus University Rotterdam; Erasmus MC; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard Medical School; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; Howard Hughes Medical Institute; University of Texas Southwestern Medical Center; Jackson Laboratory; Imperial College London; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Wurzburg
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adp7361
• 发表日期: 2025-09-04
• 页码: 1043-1048
• 关键词: ACUTE CORONARY SYNDROME; MYOCARDIAL-ISCHEMIA; single-cell; BORDER ZONE; macrophages; arrhythmia; tracking; reperfusion; neutrophils; mechanisms

摘要

Ventricular tachycardia disrupts the heart's coordinated pump function, leading to sudden cardiac death. Neutrophils, which are recruited in high numbers to the ischemic myocardium, promote these arrhythmias. Comparing neutrophils with macrophages, we found that resistin-like molecule gamma (Retnlg or RELM gamma) was the most differentially expressed gene in mouse infarcts. RELM gamma is part of a pore-forming protein family that defends the host against bacteria by perforating their membranes. In mice with acute infarcts, leukocyte-specific Retnlg deletion reduced ventricular tachycardia. RELM gamma elicited membrane defects that allowed cell exclusion dyes to enter the cardiomyocyte interior and also caused delayed afterdepolarizations and later cardiomyocyte death, both of which are strong arrhythmogenic triggers. Human resistin likewise attacked membranes of liposomes and mammalian cells. We describe how misdirected innate immune defense produces membrane leaks and ventricular arrhythmia.