A5065564870- Cardiac Valve Diseases and Treatments
- Urinary Bladder and Prostate Research
- Antibiotics Pharmacokinetics and Efficacy
- Lipoproteins and Cardiovascular Health
- Urinary Tract Infections Management
- Extracellular vesicles in disease
- Infective Endocarditis Diagnosis and Management
- Receptor Mechanisms and Signaling
- PARP inhibition in cancer therapy
- Caveolin-1 and cellular processes
- Liver Disease Diagnosis and Treatment
- Hormonal and reproductive studies
- Metabolism and Genetic Disorders
- RNA and protein synthesis mechanisms
- Parathyroid Disorders and Treatments
- Atherosclerosis and Cardiovascular Diseases
- Neuropeptides and Animal Physiology
- RNA modifications and cancer
- Toxin Mechanisms and Immunotoxins
- Peroxisome Proliferator-Activated Receptors
- Aortic Thrombus and Embolism
- Neonatal Health and Biochemistry
- Drug-Induced Hepatotoxicity and Protection
- Cardiovascular Effects of Exercise
- Eicosanoids and Hypertension Pharmacology
Brigham and Women's Hospital
2020-2025
Harvard University
2020-2025
University of Shizuoka
2011-2019
Abstract Aims Calcific aortic valve disease (CAVD) is the most common disease, which consists of a chronic interplay inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as novel key player in pathophysiology CAVD, its role transformation valvular interstitial cells (VICs) into pathological phenotypes explored. Methods results An (AV) wire injury (AVWI) mouse model with deficiency used to determine effects on AV stenosis, vitro experiments employed human...
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 Peripheral arterial disease (PAD) is estimated to affect 7% of the adult population in United States; however, there currently little understanding key cellular and molecular pathways at play. With PAD characterized by vascular inflammation associated calcification, current study set out elucidate role NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome activation cohort. Methods Results Global proteomics human vessels with...
Lipoprotein(a) (Lp[a]) blood levels >50 mg/dL is a major cardiovascular disease risk factor in humans. Lp(a) associates with increased calcification, critical pathology no clinically available drug therapies. The mechanisms through which increases calcification remain undefined. We hypothesized that promotes the release of calcifying extracellular vesicles (EVs) contribute to formation microcalcification tissues. Here, we show both primary human smooth muscle cells (SMCs) and valvular...
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...
Cardiovascular calcification is the lead predictor of cardiovascular events and top cause morbidity mortality worldwide. To date, only invasive surgical options are available to treat despite growing understanding underlying pathological mechanisms. Key players in vascular smooth muscle cells (SMCs), which transform into calcifying SMCs secrete mineralizing extracellular vesicles that form microcalcifications, subsequently increasing plaque instability consequential rupture. There an...
The in vivo muscarinic receptor binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction patients with overactive bladder is reviewed. Transdermal administration oxybutynin rats leads significant receptors the without long-term submaxillary gland abolishment salivation evoked by oral oxybutynin. Oral solifenacin shows long-lasting mouse tissues expressing M3 subtype. tolterodine binds more selectively than mice. imidafenacin...
Vascular calcification is a cardiovascular disorder with no therapeutic options. We recently reported that o-octanoyltransferase (CROT) suppression can inhibit vascular in vivo and vitro through amelioration of mitochondrial function fatty acid metabolism. Inhibiting small molecule compound targeting CROT-associated mechanisms will be promising non-invasive treatment calcification. Here we used computational approach to search for existing drugs the CROT pathway. For screening compounds...
Imidafenacin is a potent and selective antagonist of M<sub>1</sub> M<sub>3</sub> muscarinic receptors that safe, efficacious, well tolerated for controlling the symptoms overactive bladder (OAB). However, precise mechanisms responsible bladder-selective pharmacological effects this agent remain unclear. The in vivo pharmacologic imidafenacin result from receptor occupancy. Therefore, present study was performed to characterize binding by tritium-labeled with high specific activity...
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)...
Objectives: The current study aimed to characterize comparatively the binding of imidafenacin muscarinic receptors in human bladder mucosa and detrusor muscle parotid gland. Methods: receptor homogenates tissues (bladder gland) was measured using a radioligand assay with [N‐methyl‐ 3 H]scopolamine methyl chloride ([ H]NMS). Results: Imidafenacin competed [ H]NMS for sites gland, its affinity significantly (2.6–8.7 times) higher than that oxybutynin. Also, approximately two‐fold gland tissue....
ADP-ribosylation is a post-translational modification that catalyzed by the ADP-ribosyltransferase enzyme family. Major emphasis to date has been ADP-ribosylation's role in cancer; however, there growing interest its inflammation and cardiovascular disease. Despite recent boom mass spectrometry-based proteomics, are limited computational resources evaluate quality of reported ADP-ribosylated (ADPr) proteins. We recently developed novel spectral annotation strategy (RiboMaP) facilitates...
The present study aimed to characterize muscarinic receptor binding of fesoterodine, 5-hydroxymethyl tolterodine (5-HMT), and in bladder other tissues rats after their oral, intravenous, or intravesical administration. Muscarinic receptors were measured by using [N-methyl-3H]scopolamine methyl chloride ([3H]NMS). vitro affinity for was the highest 5-HMT, followed fesoterodine. Fesoterodine exhibited lower rat submaxillary gland than detrusor muscle urothelium. affinities 5-HMT similar among...
The present study aimed to directly characterize specific binding sites of tritium ([(3)H])-labeled imidafenacin, a new radioligand for labeling muscarinic receptors, in the bladder and other peripheral or central nervous tissues rats. Muscarinic receptors rat were measured by assay using [(3)H]imidafenacin. Specific [(3)H]imidafenacin was saturable, reversible, high affinity. Estimated dissociation constants (Kd values) significantly lower submaxillary gland prostate higher heart than...
Introduction: Carnitine O-octanoyltransferase (CROT) is a well-established peroxisomal enzyme involved in liver fatty acid oxidation, but less known about its recently discovered role promoting vascular calcification, and whether CROT-dependent metabolism contributes to the latter. To date, CROT function context of calcification potential has been conducted dyslipidemic low-density lipoprotein receptor-deficient ( Ldlr−/− ) mice. Objectives: differentiate peroxisome lipid biology from that...
Background: Inflammation and lipid accumulation are major features of atherosclerosis, a leading cause death morbidity worldwide. Our previous study recognized ADP-ribosylation, post-translational modification, as novel regulator macrophage activation. We also have established mass spectrometry-based ADP-ribosylation proteomics. Using this technology, we evaluated the completely uncharacterized role in atherogenesis. hypothesized that ADP-ribosylated proteins circulate from liver, accumulate...
Background: People living with HIV (PLWH) on anti-retroviral therapy remain at risk for cardiovascular diseases, including atherosclerosis. We hypothesized that persistent viral protein (HIV-Nef) in extracellular vesicles (EVs) modulate macrophage heterogeneity to impair atheroprotective efferocytosis accelerate disease. Methods and Results: Macrophage was characterized human primary macrophages (50,931 cells; 4 donors) stimulated EVs engineered contain HIV-Nef by simultaneous scRNAseq...
Abstract BACKGROUND Calcific aortic valve stenosis (CAVS) is a global clinical burden, impacting around 2% of the population over 65 years age. No pharmacotherapeutics exist, with surgical repair and transcatheter replacement being only intervention. Females are underrepresented in studies CAVS, leading to delay timely intervention increased mortality. Histopathology demonstrates female CAVS presents decreased valvular calcification but fibrosis severity symptoms. We hypothesize that...
ADP-ribosylation (ADPr) is a post-translational modification that best studied using mass spectrometry. Method developments are permissive with low inputs or baseline levels of protein ribosylation represent the next frontier in field. High-field asymmetric waveform ion mobility spectrometry (FAIMS) reduces peptide complexity gas phase, providing means to achieve maximal ADPr sequencing depth. We therefore investigated extent which FAIMS without traditional gas-phase fractionation-separation...
Abstract Funding Acknowledgements Type of funding sources: Other. Main source(s): Private grant from Kowa Pharmaceuticals to Brigham and Woman's Hospital Calcific aortic valve stenosis (CAVS) is the most prevent valvular heart disease in western world increasing exponentially with age, an 112% increase CAVS deaths last three decades; however no therapeutic treatment currently available. Recently, lipoprotein(a) [Lp(a)] has been demonstrated be independent causal risk factor for CAVS, yet...