Necroptosis is a key contributor to impaired cardiac repair following myocardial infarction.

Authors

Razoan Al Rimon, Yingxi Li, Ilamaran Meganathan, Faqi Wang, Allan G Murray, Gavin Y Oudit, Slava Epelman, Xavier Clemente-Casares, Zamaneh Kassiri

Published in

Cell death & disease. Volume 17. Issue 1. Jun 15, 2026. Epub Jun 15, 2026.

Abstract

Myocardial infarction (MI) is a leading cause of morbidity and death worldwide. Endothelial cells (ECs) contribute to post-MI remodeling through angiogenesis, inflammation, and endothelial-to-mesenchymal transition (EndMT). ADAM17, a membrane-bound protease, is upregulated in ischemic heart disease, but its role in endothelial function post-MI is unknown. We investigated whether loss of endothelial ADAM17 could improve post-MI recovery using male and female mice with inducible endothelial-specific ADAM17 knockdown (Adam17^f/f/Cdhr5-Cre^ERT2; Adam17^EC-KD). Surprisingly, male Adam17^EC-KD mice exhibited compromised post-MI survival (42% death due to LV rupture vs. 13%), and progressive decline in cardiac function compared to controls (Adam17^f/f-MI). Post-MI rupture was less drastic but detected in female Adam17^EC-KD-MI mice. Adam17^EC-KD hearts exhibited increased neutrophil infiltration, NETosis, and cytotoxic CD8⁺ T-cell accumulation post-MI; however, depletion of these immune cells did not improve post-MI survival. Single-nuclei RNA-seq analyses identified suppression of pro-angiogenic and EndMT markers, and emergence of an EC subpopulation enriched for necroptotic markers. Decreased vascularization was confirmed in the infarcted myocardium with reduced coronary density (CD31 staining; 3-D micro-CT) and pVEGFR2 signaling. Suppressed EndMT in Adam17^EC-KD mice was linked to reduced collagen crosslinking, decreased activation of the SMAD pathway (pSMAD2/3), decreased expression of lysyl oxidase and Fibronectin in infarcted myocardium. In EC-fibroblast co-cultures in vitro, endothelial Adam17 knockdown suppressed tubular formation in hypoxic conditions and reduced EndMT. Conditioned media from hypoxic EC^Ad17-KD suppressed fibroblast activation. Increased necroptosis in vivo (Adam17^EC-KD-MI), and in vitro (EC^Ad17-KD±hypoxia), was associated with increased TNFR1-RIPK3-RIPK1-MLKL signaling due to stabilization of TNFR1 in the absence of its ADAM17-mediated shedding. The critical role of necroptosis in impaired post-MI recovery was confirmed as inhibition of necroptosis (necrostatin-1) markedly improved post-MI survival and coronary vascularization in Adam17^EC-KD-MI hearts. This study demonstrates that ADAM17 regulates post-MI endothelial functions, necroptosis, vascularization, and EndMT, with necroptosis as a critical factor in post-MI adverse myocardial remodeling and survival.

PMID:
42297768
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.

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