Kumowski N., Pabel S., Grune J., Momin N., Ninh VK., Stengel L., Mentkowski KI., Iwamoto Y., Zheng Y., Lee I-H., Matthias J., Wirth JO., Pulous FE., Seung H., Paccalet A., Muse CG., Ting KKY., Delgado P., Lewis AJM., Kaushal V., Kreso A., Brown D., Hayat S., Kramann R., Swirski FK., Naxerova K., Propheter DC., Hooper LV., Moskowitz MA., King KR., Rosenthal N., Hulsmans M., Nahrendorf M.

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.

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

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