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

Nina Kumowski^{1

2

3}, Steffen Pabel^{1

2

3

4}, Jana Grune^{1

2}, Noor Momin^{1

2}, Van K Ninh⁵, Laura Stengel^{4

6}, Kyle I Mentkowski^{1

2

3}, Yoshiko Iwamoto^{1

2}, Yi Zheng², I-Hsiu Lee^{1

2

3}, Jessica Matthias⁷, Jan O Wirth⁷, Fadi E Pulous^{1

2}, Hana Seung^{1

2

3}, Alexandre Paccalet^{1

2

3}, Charlotte G Muse^{1

2

3}, Kenneth K Y Ting^{1

2

3}, Paul Delgado^{1

2}, Andrew J M Lewis⁸, Vaishali Kaushal⁹, Antonia Kreso⁹, Dennis Brown¹⁰, Sikander Hayat¹¹, Rafael Kramann^{11

12}, Filip K Swirski¹³, Kamila Naxerova^{1

14}, Daniel C Propheter¹⁵, Lora V Hooper^{15

16}, Michael A Moskowitz^{1

2

3}, Kevin R King⁵, Nadia Rosenthal^{17

18}, Maarten Hulsmans^{1

2}, Matthias Nahrendorf^{1

2

3

19

20}

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Center for Inflammation Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
⁵ University of California, San Diego Department of Medicine and Bioengineering, La Jolla, CA, USA.
⁶ Department of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany.
⁷ Abberior Instruments America, Bethesda, MD, USA.
⁸ Radcliffe Department of Medicine, NIHR Biomedical Research Centre, University of Oxford, and British Heart Foundation Centre of Research Excellence, Oxford, UK.
⁹ Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Program in Membrane Biology, Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology Hypertension), RWTH Aachen, Medical Faculty, Aachen, Germany.
¹² Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.
¹³ Cardiovascular Research Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Blavatnik Institute, Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ The Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁷ The Jackson Laboratory, Bar Harbor, ME, USA.
¹⁸ National Heart and Lung Institute, Imperial College, London, UK.
¹⁹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁰ Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany.

PMID: 40906843
DOI: 10.1126/science.adp7361

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

Nina Kumowski et al. Science. 2025.

. 2025 Sep 4;389(6764):1043-1048.

doi: 10.1126/science.adp7361. Epub 2025 Sep 4.

Authors

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Center for Inflammation Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
⁵ University of California, San Diego Department of Medicine and Bioengineering, La Jolla, CA, USA.
⁶ Department of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany.
⁷ Abberior Instruments America, Bethesda, MD, USA.
⁸ Radcliffe Department of Medicine, NIHR Biomedical Research Centre, University of Oxford, and British Heart Foundation Centre of Research Excellence, Oxford, UK.
⁹ Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Program in Membrane Biology, Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹¹ Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology Hypertension), RWTH Aachen, Medical Faculty, Aachen, Germany.
¹² Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.
¹³ Cardiovascular Research Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Blavatnik Institute, Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ The Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁷ The Jackson Laboratory, Bar Harbor, ME, USA.
¹⁸ National Heart and Lung Institute, Imperial College, London, UK.
¹⁹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁰ Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany.

PMID: 40906843
DOI: 10.1126/science.adp7361

Abstract

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 (Retnlg 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 Retnlg 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.

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

Affiliations

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

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Abstract

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