Induced degradation of LDLR completely abrogated myocarditis, and dimethyl fumarate significantly reduced pyroptosis and inflammatory burden in a murine model of COVID-19 myocarditis.
Does LDLR degradation or dimethyl fumarate reduce myocarditis and pyroptosis in a mouse model of COVID-19 myocarditis?
The LDLR-osteopontin axis drives COVID-19 myocarditis through monocyte recruitment, and targeting this pathway with LDLR degradation or dimethyl fumarate reduces inflammation and pyroptosis.
COVID-19-associated myocarditis is marked by macrophage-rich inflammation and adverse cardiac outcomes, yet its mechanisms remain unclear. We developed a reproducible BSL-2 mouse model by combining cardiac-specific human low-density lipoprotein receptor (LDLR) overexpression (AAV9-cTnT-hLDLR) with chimeric SARS-CoV-2 infection in keratin 18 human angiotensin-converting enzyme 2 transgenic mice, achieving 100% penetrance of macrophage-predominant myocarditis with cardiomyocyte necrosis and gasdermin D-mediated pyroptosis. We identified a previously unrecognized high-affinity interaction between LDLR (CR2-CR5 domains) and osteopontin that drives monocyte recruitment. Induced degrader of LDLR-mediated LDLR degradation completely abrogated myocarditis, while dimethyl fumarate significantly reduced pyroptosis and inflammatory burden. Importantly, human myocarditis autopsy hearts exhibited >10-fold up-regulation of LDLR and intercellular adhesion molecule-1, mirroring the murine findings. These data establish the LDLR-osteopontin axis as a mechanistic and targetable driver of COVID-19 myocarditis and provide a translational platform for therapeutic development in viral myocarditis.
Capcha et al. (Tue,) conducted a other in COVID-19 myocarditis. Induced degrader of LDLR and dimethyl fumarate was evaluated on Myocarditis, pyroptosis, and inflammatory burden. Induced degradation of LDLR completely abrogated myocarditis, and dimethyl fumarate significantly reduced pyroptosis and inflammatory burden in a murine model of COVID-19 myocarditis.