Resistin-like molecule γ attacks cardiomyocyte membranes and promotes ventricular tachycardia
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 γ (<i>Retnlg</i> or RELMγ) was the most differentially expressed gene in mouse infarcts. RELMγ 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 <i>Retnlg</i> deletion reduced ventricular tachycardia. RELMγ 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.
Authors
- Noor Momin (ORCID: https://orcid.org/0000-0003-3145-6089)
- Yoshiko Iwamoto (ORCID: https://orcid.org/0000-0002-3723-1043)
- Daniel C. Propheter (ORCID: https://orcid.org/0000-0002-8665-0885)
- Kyle I. Mentkowski (ORCID: https://orcid.org/0000-0002-6623-2096)
- Dennis A. Brown (ORCID: https://orcid.org/0000-0002-7503-3750)
- Antonia Kreso (ORCID: https://orcid.org/0000-0003-0632-958X)
- Rafael Kramann (ORCID: https://orcid.org/0000-0003-4048-6351)
- Filip K. Świrski (ORCID: https://orcid.org/0000-0002-3163-9152)
- Charlotte G. Muse (ORCID: https://orcid.org/0000-0003-4412-0250)
- Vivek Kaushal (ORCID: https://orcid.org/0000-0002-1877-0113)
- Sikander Hayat (ORCID: https://orcid.org/0000-0001-5919-8371)
- Nadia Rosenthal (ORCID: https://orcid.org/0000-0002-7599-7365)
- Steffen Pabel (ORCID: https://orcid.org/0009-0000-1121-4889)
- Jana Grune (ORCID: https://orcid.org/0000-0001-6209-7416)
- Jan Otto Wirth (ORCID: https://orcid.org/0000-0002-6471-9626)
- Kevin R. King (ORCID: https://orcid.org/0000-0003-1472-2189)
- Lora V. Hooper (ORCID: https://orcid.org/0000-0002-2759-4641)
- Fadi E. Pulous (ORCID: https://orcid.org/0000-0002-0794-8078)
- Yi Zheng (ORCID: https://orcid.org/0009-0007-8426-8117)
- Paul Delgado (ORCID: https://orcid.org/0000-0002-4554-9924)
- Kamila Naxerova (ORCID: https://orcid.org/0000-0001-7744-5110)
- Hana Seung (ORCID: https://orcid.org/0009-0004-7754-787X)
- Maarten Hulsmans (ORCID: https://orcid.org/0000-0003-1009-658X)
- I‐Hsiu Lee (ORCID: https://orcid.org/0000-0001-7200-7867)
- Kenneth K. Y. Ting (ORCID: https://orcid.org/0000-0002-6851-7124)
- Matthias Nahrendorf (ORCID: https://orcid.org/0000-0002-4021-1887)
- Jessica Matthias (ORCID: https://orcid.org/0000-0001-6560-2174)
- Andrew Lewis (ORCID: https://orcid.org/0000-0002-3714-6711)
- Van K. Ninh (ORCID: https://orcid.org/0000-0001-6017-4035)
- Alexandre Paccalet (ORCID: https://orcid.org/0000-0002-6331-562X)
- Nina Kumowski (ORCID: https://orcid.org/0000-0003-3355-9102)
- Laura Stengel
- Michael A. Moskowitz
Institutions
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Erasmus MC (NL)
- University Hospital Regensburg (DE)
- British Heart Foundation (GB)
- Gordon Center for Medical Imaging (US)
- Massachusetts General Hospital (US)
- Jackson Laboratory (US)
- Boston VA Research Institute (US)
- Universitätsklinikum Würzburg (DE)
- Kerckhoff Klinik (DE)
- La Jolla Bioengineering Institute (US)
- Oxford BioMedica (United Kingdom) (GB)
- Center for Systems Biology (US)
- Imperial College London (GB)
- The University of Texas Southwestern Medical Center (US)
- RWTH Aachen University (DE)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science
- Published
- 2025-09-04
- DOI
- https://doi.org/10.1126/science.adp7361
- Citations
- 6
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 8.33