A5057124539- Pulmonary Hypertension Research and Treatments
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Kruppel-like factors research
- Congenital heart defects research
- Cardiovascular Function and Risk Factors
- Cardiovascular Issues in Pregnancy
- Eosinophilic Disorders and Syndromes
- Adipose Tissue and Metabolism
- COVID-19 Clinical Research Studies
- Heart Failure Treatment and Management
- Immune responses and vaccinations
- Chromatin Remodeling and Cancer
- Cardiovascular Disease and Adiposity
- Immune Response and Inflammation
- Cell Adhesion Molecules Research
- Immune cells in cancer
- Circular RNAs in diseases
- RNA modifications and cancer
- Renin-Angiotensin System Studies
- Cardiovascular and exercise physiology
- Exercise and Physiological Responses
- Ion Channels and Receptors
- NF-κB Signaling Pathways
- ATP Synthase and ATPases Research
- Calcium signaling and nucleotide metabolism
Cardiovascular Institute of the South
2016-2024
Stanford University
2016-2024
Lucile Packard Children's Hospital
2024
Nagoya City University
2024
University of Illinois Chicago
2015-2016
Cardiovascular Institute Hospital
2016
Oregon Health & Science University
2011
In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers alleviate disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features UMC iPSC-ECs related signaling or...
Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling patients at extremes severity spectrum. Here, we performed multi-omic single-cell 64 COVID-19 across full range severity, from outpatients with mild fatal cases. transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction peripheral innate immunity in severe COVID-19, including prominent...
Maintaining endothelial cells (EC) as a monolayer in the vessel wall depends on their metabolic state and gene expression profile, features influenced by contact with neighboring such pericytes smooth muscle (SMC). Failure to regenerate normal EC response injury can result occlusive neointima formation diseases atherosclerosis pulmonary arterial hypertension.We investigated nature functional importance of contact-dependent communication between SMC maintain integrity.We found that...
Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote beneficial response. We show under LSS, KLF4 interacts with SWI/SNF nucleosome remodeling complex increase accessibility at enhancer sites of homeostatic genes. By combining molecular and computational approaches discover enhancers loop promoters KLF4- LSS-responsive genes stabilize cells...
Mutations in
Rationale: Idiopathic or heritable pulmonary arterial hypertension is characterized by loss and obliteration of lung vasculature. Endothelial cell dysfunction pivotal to the pathophysiology, but different causal mechanisms may reflect a need for patient-tailored therapies.Objectives: cells differentiated from induced pluripotent stem were compared with endothelial same patients idiopathic hypertension, determine whether they shared functional abnormalities altered gene expression patterns...
Neutrophils respond to invading bacteria by adopting a polarized morphology, migrating in the correct direction, and engulfing bacteria. How neutrophils establish precisely orient this polarity toward pathogens remains unclear. Here we report that resting neutrophils, ERM (ezrin, radixin, moesin) protein moesin its active form (phosphorylated membrane bound) prevented cell polarization inhibiting small GTPases Rac, Rho, Cdc42. Attractant-induced activation of myosin phosphatase deactivated...
BackgroundPreclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation.Research QuestionAre circulating levels abnormal PAH are they associated with clinical severity?Study Design MethodsIn an observational Stanford University cohort (n = 249), plasma were measured comparison those of healthy control participants 106). measurements then related to features relevant...
Pathological high shear stress (HSS, 100 dyn/cm
ABSTRACT Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling patients at extremes severity spectrum. Here, we performed multi-omic single-cell 64 COVID-19 across full range severity, from outpatients with mild fatal cases. transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction peripheral innate immunity in severe COVID-19, most profound...
We previously reported heightened expression of the human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages patients with PA hypertension (PAH). Furthermore, recombinant dUTPase increased IL-6 endothelial cells (PAECs) caused rats. Here we show that overexpressing dUTPase, as opposed to GFP, can release extracellular vesicles (EVs) cause mice association mesenchymal...
Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities EVs to mechanisms uncovered by proteomic transcriptomic profiling. Methods: Production elastase, release traps, adhesion, migration were assessed from patients with control subjects. Proteomic analyses applied explain perturbations, data used find underlying mechanisms. CD66b-specific neutrophil isolated...
Abstract Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary (PA) endothelial cell (EC) dysfunction associated with unrepaired DNA damage. BMPR2 the most common genetic cause of PAH. We report that human PAEC reduced have persistent damage room air after hypoxia (reoxygenation), as do mice EC-specific deletion Bmpr2 (EC- -/- ) and hypertension. Similar findings are observed loss sensor ATM , Atm deleted EC ). Gene expression analysis EC- lung reveals Foxf1...
Abstract Aims The aims of this study were to evaluate the effects sodium tanshinone IIA sulfonate (STS) on left ventricular (LV) remodelling after for ST‐elevated myocardial infarction (STEMI). Methods and results In prospective, randomized clinical trial, 101 patients with MI (STEMI) a successful reperfusion immediately receive STS (80 mg qd 7 days) or saline control, along standard therapy. primary effectiveness endpoint is % change in LV end diastolic volumes index (%∆ LVEDVi) as measured...
ABSTRACT TLR4 activation by LPS (endotoxin) is mediated the MyD88 and TRIF intracellular signaling pathways. We determined relative of these pathways in murine ocular tissue after exposure. Additionally, we explored whether BM-derived or non-BM-derived cells were major contributors to EIU. Mice deficient their congenic (WT) controls received 250 ng ultrapure ivt at 0 h. Ocular inflammation was assessed histological analysis 4, 6, 24 h, additionally, MyD88−/− mice, intravital microscopy...
Abstract Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote beneficial response. We show under LSS, KLF4 interacts with SWI/SNF nucleosome remodeling complex increase accessibility at enhancer sites of homeostatic genes. By combining molecular and computational approaches discovered enhancers loop promoters known novel KLF4-...
Computational modeling indicated that pathological high shear stress (HSS; 100 dyn/cm2) is generated in pulmonary arteries (PAs; 100-500 µm) congenital heart defects causing PA hypertension (PAH) and idiopathic PAH with occlusive vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) a feature of PAH. We hypothesize HSS induces EndMT, contributing to the initiation progression used Ibidi perfusion system determine whether applied human endothelial cells (ECs) EndMT when compared...
Abstract Exercise testing is routinely used in clinical practice to assess fitness - a strong predictor of survival as well causes exercise limitations. While these studies often focus on cardiopulmonary response and selected molecular pathways, the dynamic system-wide has not been fully characterized. We performed longitudinal multi-omic profiling plasma peripheral blood mononuclear cells including transcriptome, immunome, proteome, metabolome lipidome 36 well-characterized volunteers...
Neutrophils respond to invading bacteria by adopting a polarized morphology, migrating in the correct direction, and engulfing bacteria.How neutrophils establish precisely orient this polarity toward pathogens remains unclear.Here we report that resting neutrophils, ERM (ezrin, radixin, moesin) protein moesin its active form (phosphorylated membrane bound) prevented cell polarization inhibiting small GTPases Rac, Rho, Cdc42.Attractant-induced activation of myosin phosphatase deactivated at...
Pulmonary arterial hypertension (PAH) is a devastating progressive disease associated with high mortality despite current vasodilator therapies. Perivascular inflammation and levels of neutrophil elastase are thought to play pivotal role in the adverse vascular remodeling small pulmonary arteries that causes PAH. Despite this, function neutrophils particular, their interaction endothelium has not been studied We hypothesized functions such as adhesion substratum or endothelial cells...