A5029736742- Cardiac Valve Diseases and Treatments
- Aortic Disease and Treatment Approaches
- Aortic aneurysm repair treatments
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Extracellular vesicles in disease
- Connective tissue disorders research
- PARP inhibition in cancer therapy
- Peroxisome Proliferator-Activated Receptors
- Infective Endocarditis Diagnosis and Management
- Lipoproteins and Cardiovascular Health
- Metabolomics and Mass Spectrometry Studies
- Toxin Mechanisms and Immunotoxins
- Cell Adhesion Molecules Research
- Connexins and lens biology
- Endoplasmic Reticulum Stress and Disease
- Lipid metabolism and disorders
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- Folate and B Vitamins Research
- Diet and metabolism studies
- RNA and protein synthesis mechanisms
- Mass Spectrometry Techniques and Applications
- Mitochondrial Function and Pathology
- Cardiovascular Function and Risk Factors
- Metabolism, Diabetes, and Cancer
Brigham and Women's Hospital
2016-2023
Harvard University
2016-2023
Kowa (Japan)
2019
University of Toyama
2014-2018
Kawasaki Medical School
2006
Background: No pharmacological therapy exists for calcific aortic valve disease (CAVD), which confers a dismal prognosis without invasive replacement. The search therapeutics and early diagnostics is challenging because CAVD presents in multiple pathological stages. Moreover, it occurs the context of complex, multi-layered tissue architecture; rich abundant extracellular matrix phenotype; unique, highly plastic, multipotent resident cell population. Methods: A total 25 human stenotic valves...
Chronic kidney disease (CKD) increases cardiovascular risk. Underlying mechanisms, however, remain obscure. The uremic toxin indoxyl sulfate is an independent risk factor in CKD. We explored the potential impact of on proinflammatory activation macrophages and its underlying mechanisms.We examined vitro effects clinically relevant concentrations responses roles organic anion transporters transporting polypeptides (OATPs). A systems approach, involving unbiased global proteomics,...
Protein-mediated tethering of vesicles in the extracellular matrix contributes to microcalcification formation.
Objective: Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established role for calcification-prone extracellular vesicles promoting vascular calcification. However, the mechanisms by which mellitus provokes events remain incompletely understood. Our goal was to identify that increased S100A9 promotes release of from human macrophages Approach Results: Human primary exposed high glucose (25 mmol/L) secretion expression receptor...
Background: Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role in macrophage activation and vein largely unknown, especially through LDLR-independent mechanisms. This study aimed explore novel mechanism disease induced by circulating an...
BACKGROUND: Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating extracellular vesicles (EVs) act as biomarkers cardiovascular diseases, tissue-entrapped EVs are associated with early mineralization, but their cargoes, functions, and contributions to disease remain unknown. METHODS: Disease stage–specific proteomics was performed on human carotid endarterectomy specimens (n=16) stenotic...
Aortic valvular interstitial cells (VICs) isolated from patients undergoing valve replacement are commonly used as
Calcific aortic valve disease (CAVD) occurs when subpopulations of cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein–lowering therapies have failed in clinical trials, there are currently no pharmacological interventions available for this disease. Apolipoproteins known promoters atherosclerosis, whether they possess pathogenic properties CAVD is...
Background: The ascending aorta is a common location for aneurysm and dissection. This aortic region populated by mosaic of medial adventitial cells that are embryonically derived from either the second heart field (SHF) or cardiac neural crest. SHF-derived populate areas coincide with spatial specificity thoracic aortopathies. purpose this study was to determine whether how contribute Methods: Ascending pathologies were examined in patients sporadic aortopathies angiotensin II...
Cellular heterogeneity of aortic valves complicates the mechanistic evaluation calcification processes in calcific valve disease (CAVD), and animal models are lacking. In this study, we identify a disease-driver population (DDP) within valvular interstitial cells (VICs). Through stepwise single-cell analysis, phenotype-guided omic profiling, network-based characterize DDP fingerprint as CD44highCD29+CD59+CD73+CD45low discover potential key regulators human CAVD. These DDP-VICs demonstrate...
ADP-ribosylation is a post-translational modification that, until recently, has remained elusive to study at the cellular level. Previously dependent on radioactive tracers identify targets, several advances in mass spectrometric workflows now permit global identification of ADP-ribosylated substrates. In this study, we capitalized two enrichment strategies, and multiple activation methods performed Orbitrap Fusion Lumos, IFN-γ-induced substrates macrophages. The ADP-ribosyl binding protein,...
Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release incorporation of trafficking vesicles mediates secretion degradation. We hypothesized that ER drives mitochondrial fission proteostasis.
Objective: Vascular calcification is a critical pathology associated with increased cardiovascular event risk, but there are no Food and Drug Administration-approved anticalcific therapies. We hypothesized validated that an unbiased screening approach would identify novel mediators of human vascular calcification. Approach Results: performed quantitative proteomics pathway network analysis identified CROT (carnitine O-octanoyltransferase) in calcifying primary coronary artery smooth muscle...
Objective: Clinical evidence has linked low HDL (high-density lipoprotein) cholesterol levels with high cardiovascular disease risk; however, its significance as a therapeutic target remains unestablished. We hypothesize that HDLs functional heterogeneity is comprised of metabolically distinct proteins, each on sizes and are affected by diet. Approach Results: Twelve participants were placed 2 healthful diets in monounsaturated fat or carbohydrate. After 4 weeks diet, completed metabolic...
Recent in vivo tracer studies demonstrated that targeted mass spectrometry (MS) on the Q Exactive Orbitrap could determine metabolism of HDL proteins 100s-fold less abundant than apolipoprotein A1 (APOA1). In this study, we demonstrate Lumos can measure whose abundances are 1000s-fold APOA1, specifically lipid transfer phospholipid protein (PLTP), cholesterol ester (CETP), and lecithin-cholesterol acyl transferase (LCAT). Relative to Exactive, improved detection by reducing enrichment...
Abdominal aortic aneurysm (AAA), characterized by a continued expansion of the aorta, leads to rupture if not surgically repaired. Mice aid study disease progression and its underlying mechanisms since sequential studies development are feasible in humans. The present used unbiased proteomics systems biology understand molecular relationship between mouse models AAA human disease.Aortic tissues developing established aneurysms produced either angiotensin II (AngII) infusion Apoe-/- Ldlr-/-...
Apolipoprotein A4's (APOA4's) functions on HDL in humans are not well understood. A unique feature of APOA4 is that it an intestinal apolipoprotein secreted and chylomicrons. The goal this study was to gain a better understanding the origin function by studying its metabolism across 6 sizes. Twelve participants completed metabolic tracer study. isolated APOA1 immunopurification separated size. Tracer enrichments for were determined targeted mass spectrometry, rates derived compartmental...
Abstract Background Fewer than 50% of patients develop calcification both atherosclerotic plaques and aortic valves, implying differential pathogenesis. While circulating extracellular vesicles (EVs) act as biomarkers cardiovascular diseases, tissue-entrapped EVs associate with early mineralization, but their contents, function, contributions to disease remain unknown. Results Global proteomics human carotid artery endarterectomies calcified valves from a total 27 donors/patients revealed...
Objective: Aortic valve (AV) leaflets rely on a precise extracellular matrix (ECM) microarchitecture for appropriate biomechanical performance. The ECM structure is maintained by valvular interstitial cells (VICs), which reside within the leaflets. presence of pigment produced melanocytic population VICs in mice with dark coats has been generally regarded as nuisance, it interferes histological analysis AV However, our previous studies have shown that correlates increased mechanical...
Mass-spectrometry-enabled ADP-ribosylation workflows are developing rapidly, providing researchers a variety of ADP-ribosylome enrichment strategies and mass spectrometric acquisition options. Despite the growth spurt in upstream technologies, systematic ADP-ribosyl (ADPr) peptide spectral annotation methods lacking. HCD-dependent studies common, but resulting MS2 spectra complex, owing to mixture b/y-ions m/p-ion peaks representing one or more dissociation events ADPr moiety (m-ion)...
We developed an automated quantification workflow for PRM‐enabled detection of D3‐Leu labeled apoA‐I in high‐density lipoprotein (HDL) isolated from humans. Subjects received a bolus injection and blood was drawn at eight time points over three days. HDL separated into six size fractions subsequent proteolysis PRM analysis the signal ∼0.03 to 0.6% enrichment. implemented intensity‐based approach that takes advantage high‐resolution/accurate mass scans identify 2HM3 ion non‐specific peaks....