Endothelial-specific ADAM17 knockdown in male mice compromised post-MI survival, causing 42% death due to LV rupture versus 13% in controls, driven by increased necroptosis.
Endothelial ADAM17 is critical for post-MI recovery, as its loss exacerbates necroptosis, impairs vascularization and EndMT, and increases mortality due to LV rupture.
Absolute Event Rate: 42% vs 13%
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.
Rimon et al. (Mon,) conducted a other in Myocardial infarction. Endothelial-specific ADAM17 knockdown vs. Controls (Adam17 f/f -MI) was evaluated on Death due to LV rupture. Endothelial-specific ADAM17 knockdown in male mice compromised post-MI survival, causing 42% death due to LV rupture versus 13% in controls, driven by increased necroptosis.