Document text
Principal Investigator: Lina A Shehadeh
Organization: MIAMI VA HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
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).
Terms: <1,2-diacylglycerol><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2aR phosphoprotein I><2ar peptide><ACE2><AKT><Affinity><Agonist><Akt protein><Apopain><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 3><Attenuated><Autopsy><Binding><Blood><Blood Reticuloendothelial System><Blood monocyte><Body Tissues><CASP-3><CASP3><CASP3 gene><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CPP-32><CPP32><CPP32 protein><CPP32B><CPP32beta><CV-19><Cardiac><Cardiac Block><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiovascular Diseases><Cell Body><Cell Line><Cell surface><CellLine><Cells><Clinic><Clinical><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Complex><Coronavirus Infectious Disease 2019><Cysteine Protease CPP32><Cysteine Protease CPP32 Gene><Data><Data Bases><Databases><Deposit><Deposition><Diacylglycerols><Diglycerides><Disease Progression><EFRAC><Ejection Fraction><Eta-1 protein><Eta-1-Op protein><Female><Genetic><HPLC><Healthcare><Heart><Heart Block><Heart Muscle Cells><Heart failure><Heart myocyte><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Host Factor><Host Factor Protein><Immune infiltrates><Immunoglobulin Enhancer-Binding Protein><In Vitro><Infection><Inflammatory><Inflammatory Response><Integration Host Factors><K-18><K-18 conjugate><K18><K18 combination><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Receptors><Lipids><Lipoprotein LDL Receptors><Low Density Lipoprotein Cholesterol><Low Density Lipoprotein Receptor><Luciferase Immunologic><Luciferases><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance Imaging><Marrow monocyte><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medical center><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modeling><Molecular Interaction><Murine><Mus><Myocarditis><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><NMR Imaging><NMR Tomography><NRP1><NRP1 gene><Non-Polyadenylated RNA><Nuclear Factor kappa B><Nuclear Magnetic Resonance Imaging><Nuclear Transcription Factor NF-kB><PARP Cleavage Protease><PARP Cleavage Protease Gene><Patients><Peptides><Persons><Predisposition><Prevention><Programmed Cell Death><Proliferating><Protein Analysis><Protein Kinase B><Proteins><Proto-Oncogene Proteins c-akt><Publishing><RAC-PK protein><RNA><RNA Gene Products><RNA immunization><RNA vaccination><Receptor Inhibition><Receptor Protein><Reporting><Ribonucleic Acid><Role><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCA-1><SCA-1 Gene><SREBP Cleavage Activity 1><SREBP Cleavage Activity 1 Gene><Sampling><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Strains Cell Lines><Susceptibility><Symptoms><Syndrome><Thesaurismosis><Tissues><Transcription Factor NF-kB><United States Department of Veterans Affairs><United States Veterans Administration><VEGF165R><Veterans Administration><Veterans Affairs><Wild Type Mouse><Wuhan coronavirus><Yama><Yama protein><Zeugmatography><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><angiotensin converting enzyme 2><angiotensin converting enzyme II><attenuate><attenuates><beta-Lipoprotein Cholesterol><bone sialoprotein 1><bone sialoprotein I><c-akt protein><cardiac failure><cardiac inflammation><cardiomyocyte><cardiovascular disorder><caspase-3><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cultured cell line><cysteine protease P32><cytokine><cytotoxic><data base><determine efficacy><diacylglycerol><diglyceride><early T-lympocyte activation-1 protein><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><fat metabolism><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><hCoV19><health care><immune cell infiltrate><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inhibitor><intraperitoneal><intravenous injection><kappa B Enhancer Binding Protein><lipid metabolism><live cell image><live cell imaging><live cellular image><live cellular imaging><mRNA immunization><mRNA vaccination><male><metabolism disorder><migration><monocyte><mouse model><murine model><nCoV2><necropsy><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nuclear factor kappa beta><osteopontin><overexpress><overexpression><pharmacologic><post SARS-CoV-2 infection><postmortem><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><protein complex><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><receptor><receptor binding><receptor bound><related to A and C-protein><response><secreted phosphoprotein 1><sialoprotein 1><social role><spike proteins on SARS-CoV-2><therapeutic target><uptake><wildtype mouse>