Role of LDLR in COVID-Induced Myocarditis

Myocarditis associated with COVID-19 infection, long COVID syndrome and COVID mRNA vaccination have emerged as urgent unmet clinical needs. Two recent studies involving >80-million persons including national healthcare databases from the US Department of Veteran Affairs confirmed that SARS-CoV-2 infection and/or mRNA vaccination significantly predispose patients from high susceptibility as cardiovascular disease to myocarditis. Our group recently reported that levels of cardiac low-density lipoprotein receptor (LDLR) are elevated in patients with heart failure, as well as in autopsy samples from a hyper-inflammatory long COVID case. Considering this evidence, high levels of cardiac LDLR might induce lipid metabolism disorders and cytotoxic effects by increasing lipid species. In published and preliminary results described below we identified the cardiac LDLR as a myocarditis-facilitating SARS-CoV-2 receptor and a novel therapeutic target for myocarditis; our evidence includes: 1) LDLR binds the SARS-CoV-2 Spike RBD with an in vitro affinity comparable to that of NRP1 binding to a synthetic S1 peptide, 2) LDLR complexes with hACE2, 3) Overexpression (OE) of cardiomyocyte (CM)-specific hLDLR in wild type causes deposition of lipid species in the heart especially Diacylglycerol (DAG) and induces severe myocarditis with typical immune cell infiltration 4) OE of CM-specific Induced Degrader of LDLR (hIDOL) in K18-hACE2tg mice infected with chSARS-CoV-2 reduces cardiac immune cell infiltration. 5) hLDLR OE increases chSARS-CoV-2 infection in vitro, 6) IDOL activator and LXR agonist GW3965 reduces chSARS-CoV-2 infection in vitro, 7) p-AKT inhibitor Triciribine (TCN), reduces LDL-cholesterol uptake and chSARS-CoV-2 infection in vitro. Together, these findings provide a new mouse model of COVID-induced myocarditis and inspire investigating the LDLR blockers as therapeutic targets (Aim1), and the mechanisms of action via LDLR-mediated chemoattraction of OPN+ve monocytes (Aim2) or DAG lipid deposition (Aim3).