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Principal Investigator: ROBERT L DANNER
Organization: CLINICAL CENTER
Fiscal Year: 2021
Funding agency: NIH Clinical Center
Nitric oxide (NO): NO up-regulates TNFa production (J Immunol 1994; Blood 1997) through a cGMP-independent pathway (J Biol Chem 1997) utilizing NO-responsive Sp1 promoter binding sites (J Biol Chem 1999; J Biol Chem 2003). Dysfunctional eNOS upregulates TNFa (J Biol Chem 2000) through ROS and ERK1/2 (Am J Physiol 2001). NO activation of p38 MAPK stabilizes IL-8 mRNA (J Infect Dis 1998; J Leuk Biol 2004). NO has diverse effects on transcript stability and translation (Nucleic Acids Research 2006; J Leuk Biol 2008).
Sickle cell disease causes oxidant and inflammatory stress in the vasculature (Blood, 2004). This circulatory stress alters gene expression and arginine metabolism (Circulation, 2007).
NO anti-proliferative effects linked to p38 MAPK activation and p21 mRNA stabilization (BMC Genomics 2005; J Biol Chem 2006). NO and peroxisome proliferator-activated receptors (PPARs) protect endothelium and regulate its function. PPARg is activated by NO through p38 MAPK signaling (FASEB J 2007). In contrast to pro-inflammatory effects of high output NO, CO blocks proximal events in NF-kB signaling, broadly suppressing inflammation (PLoS One 2009).
Nuclear receptors (NRs): GR suppresses inflammation by tethering to DNA-bound NF-kB and AP-1 complexes that broadly control the expression of cytokines, chemokines and adhesion molecules. Other NRs including PPARg, MR, AR, and COUP-TF also regulate inflammation in human endothelial cells (ECs).
Rosiglitazone (RGZ) is a PPARg ligand/agonist used to treat type 2 diabetes. G-protein coupled receptor 40 (GPR40)/p38 MAPK/PGC1a/EP300 activation by RGZ was shown in human ECs to augment RGZ/PPARg genomic signaling (J Biol Chem 2015). Cognate GPR and nuclear receptor signaling networks may explain differences in the safety and efficacy of NR targeted drugs (Pharm Research 2016).
MR agonists repressed NF-kB mediated gene transcription, but trans-activated inflammatory AP-1 signaling in a DNA sequence, MR conformation, and AP-1 family member dependent fashion (J Biol Chem 2016). Aldosterone/MR activation of AP-1 may contribute to harmful inflammatory effects in CHF and PAH.
Long-chain monounsaturated fatty acids (LCMUFA; i.e., C20:1 and C22:1) benefits were associated with PPAR activation, possibly via the activation of GPR40, and favorable alterations in lipoproteins (Atheroscelerosis 2017).
SPL, but not eplerenone was found to suppress both NF-kB and AP-1 inflammatory signaling independent of MR through the proteasomal degradation of XPB, a core subunit of the eukaryotic basal transcription TFIIH complex (Cardiovasc Res 2018).
Pulmonary arterial hypertension (PAH): Two clinical protocols, including a pilot study of spironolactone therapy (Trials 2013) and a natural history study investigating circulating markers of vascular inflammation and high-resolution cardiac magnetic resonance imaging (MRI), provide a source of patient specimens to support ongoing laboratory studies.
Circulating ECs were identified by flow cytometry and their endothelial phenotype was validated using ultramicro analytical immunochemistry (Thrombosis and Haemostasis 2014).
ECs with heterogeneous PAH-associated molecular defects including BMPR2, CAV1 and SMAD9, PHD2 (prolyl hydroxylase domain protein 2; EGLN1), COUPTF2 (NR2F2), and G6PC3 (glucose-6- phosphatase catalytic subunit 3) are being studied in vitro to create a comprehensive picture of pathogenic mechanisms and therapeutic targets.
Loss-of-function mutations in bone morphogenetic protein type II receptor (BMPR2) are the most common genetic cause of PAH. BMPR2 knockdown (KD) in human pulmonary artery ECs (PAECs) activated Ras/Raf/ERK signaling, an oncogenic pathway, leading to proliferation, invasiveness and cytoskeletal abnormalities (Am J Physiol Lung Cell Mol Physiol 2016).
A meta-analysis of peripheral blood mononuclear cell (PBMC) expression profiling in PAH patients from multiple centers and across various expression profiling platforms identified an interferon-driven systemic immunologic response as a fundamental component of PAH pathobiology that was previously unrecognized in the individual blood expression profiling studies (Am J Physiol Lung Cell Mol Physiol 2020).
Caveolin-1 (CAV1) loss-of-function (LOF), similar to BMPR2, produced a proliferative, hyper- migratory and inflammatory PAEC phenotype (Grover Conference 2015; ATS 2017) with activation of JAK/STAT/interferon signaling and AKT. This inflammatory signature was also found in fibroblasts from PAH patients with CAV1 mutations and in CAV1-/- mice (Aspen Lung Conference 2019; ATS
2017). Moreover, immunofluorescence staining revealed endothelial CAV1 loss and STAT1 activation in the pulmonary arterioles of patients with idiopathic PAH, suggesting that this paradigm might not be limited to rare CAV1 frameshift mutations. While blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways simultaneously. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling and NOS3 dysregulation in the inflammatory phenotype associated with CAV1 loss (Proc Natl Acad Sci U S A 2021).
A sugen (SU5416) hypoxia rat model of pulmonary arterial hypertension has been established and an initial study of spironolactone and eplerenone compared to placebo has been completed (AHA Meeting 2019; MS submitted 2021).
Loss-of-function mutations in COUPTF2 (NR2F2) have been associated with congenital heart disease (CHD), which can result in PAH. COUPTF2 silencing in ECs produced an interferon inflammatory response and exhibited a hyper-proliferative, apoptosis-resistant, and invasive phenotype with AKT activation. Dickkopf-1 (DKK1), an upstream regulator of AKT, was induced by COUPTF2 silencing and DKK1 knockdown abrogated the abnormal signaling associated with COUPTF2 loss (Aspen Lung Conference 2019: MS in preparation).
SMAD9 LOF in human PAECs also produced an abnormal cellular phenotype characterized by proliferation, hypermigration, cytoskeletal and mitochondrial alterations and endothelial to mesenchymal transition, as well as non-canonical activation of AKT, ERK and p38 (ATS 2018; MS in preparation).
An in vitro pseudohypoxia model of PAH was established by silencing PHD2 (prolyl hydroxylase domain protein 2; EGLN1) in LMVECs. PHD2-silencing stabilized HIF2alpha, decreased ASK- interacting protein 1 (AIP; DAB2IP), and activated AKT and ERK (Aspen Lung Conference 2019; MS in preparation).
Marked resistance to apoptosis has been a consistent feature of our endothelial cell models of PAH. Using the BMPR2 loss-of-function model as a prototype, apoptosis resistance was linked to vasohibin 1 (VASH1) and DLL4 loss, PI3K/AKT and ERK activation, and JNK suppression, (Aspen Lung Conference 2019: MS in preparation). Inhibiting PI3K/AKT restored apoptosis sensitivity in the three model systems tested to date, BMPR2, CAV1 and PHD2. More recently, increased alpha-tubulin tyrosination was implicated in BMPR2 loss-associated endothelial dysfunction.
Severe cardiovascular complications, major thrombotic events and widespread organ injury from microvascular disease contribute to the morbidity and mortality of COVID-19. As such, understanding the mechanisms by which SARS-CoV-2 causes endothelial dysfunction and injury in myriad vascular beds is necessary to prevent or treat COVID-19 vasculopathy. To address this unmet need, we are investigating the effects of ACE2 and CD147 loss on human pulmonary artery endothelial cell (PAEC) function. Preliminary findings suggest that ACE2 and CD147 loss in severe COVID-19 results in a thrombogenic vasculopathy secondary to an inflammatory and dysfunctional endothelium.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><22kD Caveolae Protein><3-10C><ACE2><AIDS Virus><AKT><AMCF-I><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ARP1 protein><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Activator Protein-1><Active Oxygen><Acute><Address><Adhesion Molecule><Adult-Onset Diabetes Mellitus><Affect><Agonist><Akt protein><Aldosterone><Apoptosis><Apoptosis Pathway><Arginine><Avandia><BMPR-II><BMPR2><BMPR2 gene><BNOS><BRK-3 protein><BTF2><BTF2 transcription factor><Binding Sites><Biologic Models><Biological Models><Blood><Blood Circulation><Blood Reticuloendothelial System><Blood Vessels><Bloodstream><Bone Morphogenetic Protein Receptor, Type II (Serine/Threonine Kinase) Gene><C-jun Amino-Terminal Kinase><C-jun Kinase-1><C-jun N-Terminal Kinase 1><COUP transcription factor><COUP transcription factor II><COUP-TF><COUP-TF II><COUP-TFII><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 mortality><COVID-19 prevention><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 prevention><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 therapy><COVID19 treatment><COVID19 virus><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><CXCL8><Cancers><Cardiac><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Caveolin 1, Caveolae Protein, 22kD><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Communication and Signaling><Cell Function><Cell Process><Cell Signaling><Cell model><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular model><Cessation of life><Chemotactic Cytokines><Chronic><Circulation><Clinical Protocols><CoV-2><CoV2><Combining Site><Common Rat Strains><Complex><Cyclic GMP><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><D-Glucose-6-phosphate phosphohydrolase><DNA Binding><DNA Binding Interaction><DNA Sequence><DNA bound><Death><Defect><Disease><Disease Progression><Disorder><Drug Targeting><E1A Binding Protein p300><EDRF Synthase><ENOS><EP300><EP300 gene><ERCC3><ERCC3 gene><ERK 1><ERK1><ERK1 Kinase><Endogenous Nitrate Vasodilator><Endothelial Cells><Endothelial Nitric Oxide Synthase><Endothelium><Endothelium-Derived Growth Factor Synthase><Endothelium-Derived Nitric Oxide><Enhancer-Binding Protein AP1><Event><Excision Repair Cross-Complementation Group 3><Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 3><Exhibits><Expression Profiling><Extracellular Signal-Regulated Kinase 1><Extracellular Signal-Regulated Kinase Gene><Failure><Family member><Female><Fibroblasts><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frame Shift Mutation><Frameshift Mutation><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><G6PC3><G6PC3 gene><G6Pase-Beta><GCP1><GPCR><GTF2H><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genetic><Genetic Alteration><Genetic Change><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic defect><Genomics><Glucose-6-Phosphatase, Beta><Glucose-6-Phosphatase, Catalytic, 3><Glucose-6-Phosphate Phosphohydrolase><Goals><Guanosine Cyclic Monophosphate><Guanylyl Cyclase-Activating Factor Synthase><HIV><Hb SS disease><HbSS disease><Heart Vascular><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemostasis><Hemostatic function><Homologous Chemotactic Cytokines><Human><Human Immunodeficiency Viruses><Hypoxia><Hypoxic><IFN><IL-8><IL8><IL8 gene><Immune response><Immunochemistry><Immunofluorescence><Immunofluorescence Immunologic><Immunoglobulin Enhancer-Binding Protein><Immunological response><Impairment><In Vitro><Individual><Inflammation><Inflammatory><Inflammatory Response><Inherited Predisposition><Inherited Susceptibility><Injury><Intercrines><Interferons><Intermediary Metabolism><Interruption><Intracellular Communication and Signaling><Investigation><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><K60><KAT3B><Ketosis-Resistant Diabetes Mellitus><L-Arginine><LAV-HTLV-III><Laboratory Study><Ligands><Link><Lipoproteins><Lung><Lung Respiratory System><Lymphadenopathy-Associated Virus><MAP Kinase 3><MAP Kinase 8><MAP Kinase 8 Gene><MAP Kinase Gene><MAPK><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><MAPK3><MAPK3 Mitogen-Activated Protein Kinase><MAPK3 gene><MAPK8><MAPK8 Mitogen-Activated Protein Kinase><MAPK8 gene><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Malignant Neoplasms><Malignant Tumor><Maturity-Onset Diabetes Mellitus><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mesenchymal><Messenger RNA><Meta-Analysis><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microvascular Dysfunction><Mitochondria><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase 3><Mitogen-Activated Protein Kinase 3 Gene><Mitogen-Activated Protein Kinase 8><Mitogen-Activated Protein Kinase Gene><Model System><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mononitrogen Monoxide><Monounsaturated Fatty Acids><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><Mxi2><NC-NOS><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIDDM><NMR Imaging><NMR Tomography><NNOS><NO Synthase><NOS 1 protein><NOS type I><NOS1 protein><NOS3><NOS3 gene><NR2F2><Natural History><Neural Constitutive Nitric Oxide Synthase><Nitric Oxide><Nitric Oxide Signaling Pathway><Nitric Oxide Synthase><Nitric Oxide Synthase 3><Nitric Oxide Synthase Type I><Nitric-Oxide Synthetase><Nitrogen Monoxide><Nitrogen Protoxide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear Factor kappa B><Nuclear Magnetic Resonance Imaging><Nuclear Receptors><Nuclear Transcription Factor NF-kB><Nucleic Acids><Oncogenic><Output><Oxidants><Oxidizing Agents><Oxygen Deficiency><Oxygen Radicals><P44ERK1><PBMC><PI-3K/AKT><PI3K/AKT><PPAR><PRKM8><PSTkinase p44mpk><Pathogenesis><Pathogenicity><Pathologic><Pathway interactions><Patients><Peptide Domain><Peptidyl Prolyl Hydroxylase><Peripheral Blood Mononuclear Cell><Peroxisome Proliferator-Activated Receptors><Phenotype><Pilot Projects><Placebos><Play><Preparation><Pro-Oxidants><Procollagen Prolyl 4-Hydroxylase><Procollagen-Proline Dioxygenase><Production><Programmed Cell Death><Proline Hydroxylase><Proline,2-Oxoglutarate 4-Dioxygenase><Prolyl 4-Hydroxylase><Prolyl Hydroxylase><Protein Domains><Protein Kinase B><Proteins><Proto-Oncogene Proteins c-akt><Protocollagen Prolyl Hydroxylase><Pulmonary Artery><Pulmonary artery structure><RAC-PK protein><RAD25><RNA Expression><Ras/Raf><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Reactive Site><Reading Frame Shift Mutation><Receptor Activation><Receptor Signaling><Refractory><Relaxation><Research><Research Specimen><Resistance><Resolution><Role><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><SAPK2A><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYB8><SIS cytokines><STAT1><STAT1 gene><STAT91><SU 5416><SU5416><Safety><Scleroderma><Secondary to><Septic Shock><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 CoV 2><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Sham Treatment><Sickle Cell Anemia><Signal Pathway><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Source><Specimen><Spirolactone><Spironolactone><Stable Diabetes Mellitus><Staining method><Stains><Stress><Stress-Activated Protein Kinase 2A><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><Subcellular Process><T2 DM><T2D><T2DM><TFIIH><TSG-1><Tertiary Protein Structure><Testing><Therapeutic><Therapy trial><Thrombosis><Transcript><Transcription><Transcription Factor AP-1><Transcription Factor NF-kB><Translations><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Type III nitric oxide synthase><Tyrosine><UGRP><Ubiquitous Glucose-6-Phosphatase Catalytic Subunit-Related Protein><VIP21><VIP21 protein><Vascular Diseases><Vascular Disorder><Vascular remodeling><Ventricular><Verospirone><Virus-HIV><Work><Wuhan coronavirus><XPB><Zeugmatography><adult onset diabetes><alpha Tubulin><angiotensin converting enzyme 2><angiotensin converting enzyme II><apoAI regulatory protein-1><apolipoprotein AI regulatory protein 1><arteriole><b-ENAP><basic transcription factor 2><biological adaptation to stress><biological signal transduction><blood vessel disorder><bone morphogenetic protein receptor II><bone morphogenetic protein receptor type II><brain nitric oxide synthase><c-akt protein><c-jun N-Terminal Kinase><cGMP><caveolin 1><cell adhesion protein><chemoattractant cytokine><chemokine><chicken ovalbumin upstream promoter-transcription factor><chicken ovalbumin upstream promoter-transcription factor II><circulating biomarkers><circulating markers><circulatory system><conference><conformation><conformational state><congenital cardiac abnormality><congenital cardiac disease><congenital cardiac disorder><congenital cardiac malformation><congenital heart abnormality><congenital heart anomaly><congenital heart disease><congenital heart disorder><congenital heart malformation><constriction><convention><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 mortality><coronavirus disease 2019 prevention><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><cytokine><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><dermatosclerosis><electron acceptor><endothelial cell derived relaxing factor><endothelial dysfunction><eplerenone><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><flow cytophotometry><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome mutation><glucose-6-phosphatase><hCoV19><hemodynamics><histone acetyltransferase p300><host response><idiopathic pulmonary arterial hypertension><idiopathic pulmonary hypertension><immune system response><immunoresponse><inhibitor><inhibitor/antagonist><injuries><injury to organs><injury to the vasculature><jun-NH2-Terminal Kinase><kappa B Enhancer Binding Protein><ketosis resistant diabetes><knock-down><knockdown><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><loss of function><loss of function mutation><mRNA><malignancy><maturity onset diabetes><meetings><microvascular complications><microvascular disease><mitochondrial><mortality><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nCoV2><nNOS enzyme><neoplasm/cancer><neuronal NOS><neuronal form of nitric oxide synthase><neuronal nitric oxide synthase><nitric oxide synthase 1><nuclear factor kappa beta><nuclear receptor subfamily 2, group F, member 2><organ injury><p300><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><p44 MAPK><pathway><pilot study><prevent><prevent COVID-19><prevent COVID19><prevent coronavirus disease 2019><preventing><primary pulmonary hypertension><promoter><promotor><proto-oncogene protein RAC><proto-oncogene protein akt><prototype><pulmonary><pulmonary arterial hypertension><pulmonary artery endothelial cell><pulmonary artery hypertension><rac protein kinase><reaction; crisis><related to A and C-protein><repair><repaired><resistant><rosiglitazone><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sham therapy><sickle cell disease><sickle cell disorder><sickle disease><sicklemia><small vessel disease><social role><stress response><stress-activated protein kinase 1><stress; reaction><summit><symposia><symposium><therapeutic target><thrombogenesis><thrombogenicity><thrombotic><thrombotic disease><thrombotic disorder><transcription factor IIH><transcription factor TFIIH><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><type 2 DM><type II BMP receptor><type II DM><type two diabetes><vascular><vascular bed><vascular dysfunction><vascular inflammation><vascular injury><vasculopathy><vesicular integral membrane protein 21 kDa><α Tubulin>