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 (Adam17f/f/Cdhr5-CreERT2; Adam17EC-KD). Surprisingly, male Adam17EC-KD mice exhibited compromised post-MI survival (42% death due to LV rupture vs. 13%), and progressive decline in cardiac function compared to controls (Adam17f/f-MI). Post-MI rupture was less drastic but detected in female Adam17EC-KD-MI mice. Adam17EC-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 Adam17EC-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 ECAd17-KD suppressed fibroblast activation. Increased necroptosis in vivo (Adam17EC-KD-MI), and in vitro (ECAd17-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 Adam17EC-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.

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

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2026年6月15日

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

摘要

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.