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Principal Investigator: ROBERT L DANNER
Organization: CLINICAL CENTER
Fiscal Year: 2023
Funding agency: NIH Clinical Center
Nitric oxide (NO): NO upregulates TNFa production (J Immunol 1994; Blood 1997) through a cGMP-independent pathway (J Biol Chem 1997; J Biol Chem 1999; J Biol Chem 2003), while ROS from eNOS uncoupling upregulates TNFa (J Biol Chem 2000) through 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), altering gene expression and arginine metabolism (Circulation, 2007). NO activation of p38 MAPK stabilized p21 mRNA and was antiproliferative (BMC Genomics 2005; J Biol Chem 2006). NO activated PPARg through p38 MAPK (FASEB J 2007) protecting the endothelium. Unlike NO, CO blocked NF-kB signaling, broadly suppressing inflammation (PLoS One 2009).
Nuclear receptors (NRs): G-protein coupled receptor 40 (GPR40)/p38 MAPK/PGC1a/EP300 activation by rosiglitazone (RGZ) was shown 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). Long-chain monounsaturated fatty acids (LCMUFA; i.e., C20:1 and C22:1) benefits were associated with PPAR activation, via GPR40 activation (Atherosclerosis 2017).
MR agonists repressed NF-kB mediated gene transcription, but trans-activated 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 contribute to harm in CHF and PAH. Spironolactone (SPL) suppresses both NF-kB and AP-1 inflammatory signaling independent of MR through proteasomal degradation of XPB, a subunit of the TFIIH transcription complex (Cardiovasc Res 2018).
CFH infusions resulted in pulmonary hypertension, cardiogenic shock, and multiorgan failure, likely through NO scavenging. During sepsis, CFH infusions worsened oxygen exchange and lung injury, presumably by supplying iron that promoted bacterial growth. CFH elevation in septic shock adversely impacts sepsis outcomes through more than one mechanism that could be therapeutically targeted (Am J Physiol Heart Circ Physiol 2021).
Pulmonary arterial hypertension (PAH): A pilot study of SPL therapy (Trials 2013) and a natural history study investigating vascular inflammation support ongoing laboratory studies. Circulating ECs were identified and validated using flow cytometry and ultramicro analytical immunochemistry (Thromb Haemostasis 2014).
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 PAECs activated Ras/Raf/ERK signaling leading to proliferation, invasiveness, and cytoskeletal abnormalities (Am J Physiol Lung Cell Mol Physiol 2016).
A meta-analysis of PBMC expression profiling in PAH patients identified IFN-driven inflammation as a fundamental component of PAH pathobiology that was unrecognized in individual blood 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 associated with JAK/STAT/interferon and AKT activation. This inflammatory signature was also found in fibroblasts from PAH patients with CAV1 mutations and in CAV1-/- mice. CAV1 loss and STAT1 activation was also seen in the pulmonary arterioles of patients with idiopathic PAH. Blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling in the inflammatory phenotype associated with CAV1 loss (Proc Natl Acad Sci USA 2021).
MR antagonist treatment in the SuHx rat model of PAH preserved cardiac index and increased left ventricular (LV) end-diastolic volume index. EPL treatment blunted the induction of MR target and inflammatory response genes in the RV (Am J Physiol Lung Cell Mol Physiol 2022).
In our CAV1 loss model of PAH, NOS3 co-silencing not only blocked STAT1 and NOS3 phosphorylation, but also diminished ROS generation. Small molecule inhibitors of sAC and PKA blocked NOS3 and STAT1 phosphorylation suggesting a possible role for this pathway in CAV1 loss associated abnormalities (ATS abstract 2022).
Neither pseudotyped nor live SARS-CoV-2 virus appear to readily infect or replicate in human pulmonary ECs in vitro, with the exception of the D614G variant. Low expression of ACE2 and TMPRSS2 in PAECs may explain their diminished susceptibility to SARS-CoV-2 (ATS abstract 2022).
LOF mutations in COUPTF2 (NR2F2) have been associated with CHD, which can result in PAH. COUPTF2 silencing in ECs produced an IFN inflammatory response and a hyper-proliferative, apoptosis-resistant, and invasive phenotype. Dickkopf-1 (DKK1) was induced by COUPTF2 loss and DKK1 knockdown abrogated signaling and phenotypic abnormalities (Am J Physiol Lung Cell Mol Physiol 2023).
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 submission pending 2023).
Marked resistance to apoptosis has been a consistent feature of our EC models of PAH. Using the BMPR2 LOF model as a prototype, apoptosis resistance was linked to DLL4/NOTCH1 signaling loss with PI3K/AKT activation, and JNK suppression (Aspen Lung Conference 2019). Importantly, DLL4 loss was seen across several of our models of PAH and validated in lung tissue from iPAH patients. Blocking PI3K/AKT or PPARgamma overexpression restored apoptosis sensitivity in three model systems, BMPR2, CAV1 and PHD2 (ATS abstract 2023). Interactions among BMPR2, DLL4/NOTCH1/PPAR, and PI3K/AKT may lead to targeted approaches for treating vascular remodeling in PAH (MS pending submission 09/2023).
Vasohibin-1 (VASH1) loss with increased alpha-tubulin tyrosination was implicated in BMPR2 loss-associated cytoskeletal abnormalities and endothelial dysfunction (MS in preparation 2024). 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).
COVID-19 has acute and chronic manifestations. Endothelial senescence may underlie the thrombotic microvasculopathy associated with severe COVID-19 as well as the increased risk of cardiovascular events in patients who have otherwise recovered. We have launched a multi-institute project to investigate this hypothesis using deeply phenotyped patient cohorts, a bioengineered three-dimensional disease-on-chip in vitro system and a coronavirus mouse model. Preliminary results have demonstrated that SARS-CoV-2 viral proteins are readily taken up by human endothelium and trigger a senescent cellular phenotype (NIH Research Festival 2023; Fellows Award for Research Excellence (FARE) 2024). Endothelial senescence in this model system is reversable using a drug undergoing phase III testing in acute COVID-19.
Associate Investigator on a 2023 Bench to Bedside application: Effect of dietary fish oil enriched in very-long-chain polyunsaturated fatty acids (VLCPUFA) on cardiometabolic risk factors and visual function.
Principle Investigator on a 2023 Bench to Bedside application: Endothelial senescence in acute and late covid-19 vasculopathy.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><22kD Caveolae Protein><3-10C><3-D><3-Dimensional><3D><ACE2><AIDS Virus><AKT><AMCF-I><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ARDS><ARP1 protein><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Activator Protein-1><Active Oxygen><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Agonist><Akt protein><Aldosterone><Apoptosis><Apoptosis Pathway><Arginine><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Avandia><Award><BMPR-II><BMPR2><BMPR2 gene><BNOS><BRK-3 protein><BTF2><BTF2 transcription factor><Biologic Models><Biological Models><Biomedical Engineering><Blood><Blood Reticuloendothelial System><Blood Vessels><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 II><COUP-TF II><COUP-TFII><COVID complications><COVID related complications><COVID-19><COVID-19 complications><COVID-19 predisposition><COVID-19 related complications><COVID-19 susceptibility><COVID-19 virus><COVID-19 vulnerability><COVID19><COVID19 virus><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><CV-19><CV19><CXCL8><Cancers><Cardiac infarction><Cardiogenic Shock><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Caveolin 1, Caveolae Protein, 22kD><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Matrix><Cessation of life><Chronic><Circulation><CoV-2><CoV2><Common Rat Strains><Complex><Complication><Coronaviridae><Coronavirus><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cyclic AMP-Dependent Protein Kinases><Cyclic GMP><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><Cytoskeletal System><Cytoskeleton><DNA Sequence><Da Nang Lung><Death><Disease><Disease Progression><Disorder><Drosophila Homolog of NOTCH 1><Drug Targeting><Drugs><E1A Binding Protein p300><EDRF Synthase><ENOS><EP300><EP300 gene><ERCC3><ERCC3 gene><ERK 1><ERK1><ERK1 Kinase><Endogenous Nitrate Vasodilator><Endothelial Nitric Oxide Synthase><Endothelium><Endothelium-Derived Growth Factor Synthase><Endothelium-Derived Nitric Oxide><Enhancer-Binding Protein AP1><Epitheliasin Gene><Event><Excision Repair Cross-Complementation Group 3><Excision Repair Cross-Complementing Rodent Repair Deficiency, Complementation Group 3><Expression Profiling><Extracellular Signal-Regulated Kinase 1><Extracellular Signal-Regulated Kinase Gene><Family member><Fe element><Female><Festival><Fibroblasts><Fish Oils><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GCP1><GPCR><GTF2H><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Generalized Growth><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic defect><Genetic propensity><Genomics><Goals><Growth><Guanosine Cyclic Monophosphate><Guanylyl Cyclase-Activating Factor Synthase><HIV><Hb SS disease><HbSS disease><Heart><Heart Vascular><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemostasis><Hemostatic function><Human><Human Immunodeficiency Viruses><IFN><IL-8><IL8><IL8 gene><Immunochemistry><Immunoglobulin Enhancer-Binding Protein><Impairment><In Vitro><Individual><Inflammation><Inflammatory><Inflammatory Response><Infusion><Infusion procedures><Inherited Predisposition><Inherited Susceptibility><Injury><Interferons><Intermediary Metabolism><Interruption><Intracellular Communication and Signaling><Investigation><Investigators><Iron><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><K60><KAT3B><L-Arginine><LAV-HTLV-III><Laboratory Study><Left><Link><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><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><MOF syndrome><Malignant Neoplasms><Malignant Tumor><Mediating><Mediator><Medication><Mesenchymal><Messenger RNA><Meta-Analysis><Metabolic Processes><Metabolism><Mice><Mice Mammals><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 Configuration><Molecular Conformation><Molecular Stereochemistry><Mononitrogen Monoxide><Monounsaturated Fatty Acids><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Mutation><Mxi2><Myocardial Infarct><Myocardial Infarction><NC-NOS><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIH><NNOS><NO Synthase><NOS 1 protein><NOS type I><NOS1 protein><NOS3><NOS3 gene><NOTCH1><NOTCH1 gene><NR2F2><National Institutes of Health><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><Nuclear Factor kappa B><Nuclear Receptors><Nuclear Transcription Factor NF-kB><Nucleic Acids><O element><O2 element><Outcome><Oxidants><Oxidizing Agents><Oxygen><Oxygen Radicals><P44ERK1><PBMC><PI-3K/AKT><PI3K/AKT><PKA><PPAR><PPAR gamma><PPAR-g><PPAR-γ><PPARgamma><PPARγ><PRKM8><PRSS10><PSTkinase p44mpk><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Peptide Domain><Peptidyl Prolyl Hydroxylase><Peripheral Blood Mononuclear Cell><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Peroxisome Proliferator-Activated Receptors><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Phosphorylation><Pilot Projects><Play><Polyunsaturated Fatty Acids><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Preparation><Pro-Oxidants><Procollagen Prolyl 4-Hydroxylase><Procollagen-Proline Dioxygenase><Production><Programmed Cell Death><Proliferating><Proline Hydroxylase><Proline,2-Oxoglutarate 4-Dioxygenase><Prolyl 4-Hydroxylase><Prolyl Hydroxylase><Protein Domains><Protein Kinase A><Protein Kinase B><Protein Phosphorylation><Proteins><Proto-Oncogene Proteins c-akt><Protocollagen Prolyl Hydroxylase><Pulmonary Hypertension><RAC-PK protein><RAD25><RNA Expression><Ras/Raf><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Receptor Signaling><Refractory><Relaxation><Repression><Research><Research Personnel><Researchers><Resistance><Risk Factors><Role><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><SAPK2A><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 predisposition><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><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><STAT1><STAT1 gene><STAT91><Safety><Scleroderma><Seafood Oil><Sepsis><Septic Shock><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 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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Sickle Cell Anemia><Sight><Signal Pathway><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Spirolactone><Spironolactone><Stiff lung><Stress><Stress-Activated Protein Kinase 2A><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><Structure of parenchyma of lung><System><TAN1><TFIIH><TMPRSS2><TMPRSS2 gene><TSG-1><Tertiary Protein Structure><Therapeutic><Therapeutic Intervention><Thiazolidinedione Receptor><Tissue Growth><Transcript><Transcription><Transcription Factor AP-1><Transcription Factor NF-kB><Translations><Translocation-Associated NOTCH Homolog><Type III nitric oxide synthase><United States National Institutes of Health><VIP21><VIP21 protein><Variant><Variation><Vascular Diseases><Vascular Disorder><Vascular remodeling><Ventricular End-Diastolic Volumes><Verospirone><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus-HIV><Vision><Work><Wuhan coronavirus><XPB><alpha Tubulin><angiotensin converting enzyme 2><angiotensin converting enzyme II><antagonism><antagonist><apoAI regulatory protein-1><apolipoprotein AI regulatory protein 1><arteriole><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><b-ENAP><basic transcription factor 2><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><blood infection><blood vessel disorder><bloodstream infection><bone morphogenetic protein receptor II><bone morphogenetic protein receptor type II><brain nitric oxide synthase><c-akt protein><c-jun N-Terminal Kinase><cAMP-Dependent Protein Kinases><cGMP><cardiac infarct><cardiac preservation><cardiometabolic risk><cardiovascular risk><cardiovascular risk factor><caveolin 1><chicken ovalbumin upstream promoter-transcription factor II><circulatory system><cohort><complications due to COVID-19><conference><conformation><conformational><conformational state><conformationally><conformations><constriction><convention><corona virus><corona virus disease 2019><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><dermatosclerosis><dietary><drug/agent><electron acceptor><endothelial cell derived relaxing factor><endothelial dysfunction><flow cytophotometry><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><genome mutation><hCoV19><heart attack><heart infarct><heart infarction><heart preservation><hemodynamics><histone acetyltransferase p300><idiopathic pulmonary arterial hypertension><idiopathic pulmonary hypertension><indexing><infusions><inhibitor><injuries><injury to organs><intervention therapy><intracellular skeleton><jun-NH2-Terminal Kinase><kappa B Enhancer Binding Protein><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><lung injury><lung vascular injury><mRNA><malignancy><mitochondrial><mortality><mouse model><multiorgan failure><multiple organ system failure><murine model><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><ontogeny><organ injury><overexpress><overexpression><p300><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><p44 MAPK><pathway><phase 3 evaluation><phase 3 testing><phase III evaluation><phase III testing><pilot study><predisposed to Coronavirus disease 2019><preparations><prevent><preventing><primary pulmonary hypertension><proto-oncogene protein RAC><proto-oncogene protein akt><prototype><pulmonary><pulmonary arterial hypertension><pulmonary artery hypertension><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><pulmonary vascular injury><rac protein kinase><related to A and C-protein><repair><repaired><resistant><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><risk for stroke><risk of stroke><rosiglitazone><senescence><senescent><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 coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sickle cell disease><sickle cell disorder><sickle disease><sicklemia><small molecule inhibitor><social role><stress-activated protein kinase 1><stroke risk><summit><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><symposia><symposium><therapeutic target><three dimensional><thrombotic><transcription factor IIH><transcription factor TFIIH><translation><type II BMP receptor><vascular><vascular bed><vascular dysfunction><vascular inflammation><vasculopathy><vesicular integral membrane protein 21 kDa><virus protein><visual function><wet lung><α Tubulin>