Regulation of H2S signaling in vascular function

H2S 信号在血管功能中的调节

基本信息

批准号：
10701780
负责人：
Jay S Naik
金额：
$ 52.42万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-10 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701780
关键词：
Arteries Binding Biology Blood Vessels Blood flow Calcium Carbon Monoxide Cardiovascular Diseases Cardiovascular system Cell membrane Cell physiology Cholesterol Circulation Complex Data Disease Disparate Endothelial Cells Endothelium Event Family Functional disorder Gene Expression Goals Heme Homeostasis Hydrogen Sulfide Hypertension Impairment In Vitro Knowledge Left Mediating Membrane Membrane Lipids Mesenteric Arteries Mesentery Nitric Oxide Organ Oxygenases Pathway interactions Peripheral Vascular Diseases Phospholipid Transfer Proteins Potassium Channel Principal Investigator Production Property Proteins Regulation Reporting Resistance Role Signal Transduction Signaling Molecule Site Stroke System Testing Therapeutic Therapeutic Intervention Vanilloid Vascular Endothelial Cell Vasodilation Vasodilator Agents Work blood pressure regulation cholesterol control cholesterol trafficking genetic approach in vivo innovation meter new therapeutic target novel pharmacologic programs receptor regional difference repaired response single-cell RNA sequencing targeted treatment

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Naik, Jay, S Impaired endothelial cell (EC) function is one of the first indicators of systemic cardiovascular disease. EC dysfunction impairs local organ blood flow regulation, a primary cause of end-organ damage in most cardiovascular diseases. The discovery that ECs also synthesize carbon monoxide (CO) and hydrogen sulfide (H2S), in addition to nitric oxide (NO), which elicits vasodilation has opened a new chapter in endothelial gasotransmitter biology. While increasing evidence supports a key role for H2S in cardiovascular homeostasis, disparate findings in previous studies leaves a significant gap in knowledge on the regulation and significance of H2S signaling in the vasculature. Recently, we identified a novel regulator of H2S signaling that leads to profound differences in vasodilatory sensitivity between primary and tertiary segments of the circulation. Intriguingly, our preliminary data show that H2S dilates small (resistance) arteries in an endothelium-dependent manner at concentrations that have no effect in large arteries. However, depleting EC membrane cholesterol in large arteries unmasks H2S-mediated vasodilation, suggesting membrane lipid content and domains regulate H2S signaling. Moreover, our preliminary data show that native EC cholesterol content is greater in large arteries than resistance arteries. The concept that innate regional differences in EC membrane cholesterol content mediate functional differences in EC dilation is wholly novel, and our preliminary data (Fig. 6) demonstrate this may be caused by increased cholesterol efflux via ATP-binding cassette family a1 (Abca1) and phospholipid transfer protein (Pltp). Importantly, we have previously shown that changes in EC membrane cholesterol appear to contribute to dysfunction in disease. Therefore, EC membrane cholesterol is an important but uninvestigated variable in vascular function. The overall goal of this project is two-fold. First, to elucidate mechanisms leading to the functionally significant differences we have observed in EC membrane cholesterol content between large and small arteries. The second is to define ways in vitro and in vivo that these differences in EC membrane cholesterol control EC function, specifically H2S-induced dilation. Thus, we hypothesize that augmented cholesterol efflux in EC of resistance arteries enhances downstream H2S signaling Aim 1: Determine the mechanism(s) leading to heterogeneous membrane cholesterol content between large and small arteries. Aim 2: Determine the mechanism(s) by which membrane cholesterol regulates H2S signaling in EC. Completing the proposed studies will fill an existing knowledge gap by elucidating the regulation of H2S dilation to identify differences in EC function between small and large arteries. Conceptually, the project is very innovative in its focus on the novel ability of membrane cholesterol trafficking to act as a regulator of vasodilation. This work will increase our understanding of the fundamental properties of EC, significantly impacting our understanding of blood pressure regulation and local blood flow control, and may identify drug targets for the treatment of multiple vascular-driven diseases. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目总监/首席研究员（最后，第一，中间）：Naik，Jay，S 内皮细胞（EC）功能受损是全身心血管疾病的第一个指标之一。 EC 功能障碍会损害当地的器官血流调节，这是大多数最终器官损害的主要原因心血管疾病。 EC还合成一氧化碳（CO）和硫化氢的发现（H2S），除了一氧化氮（NO）之外，引起血管舒张还开了一个新的章节。增发剂生物学。尽管越来越多的证据支持H2在心血管稳态中的关键作用，但以前的研究中的不同发现在对调节和意义的知识方面存在很大的差距脉管系统中的H2S信号传导。最近，我们确定了H2S信号的新型调节剂，导致深刻循环的原发性和第三段段之间的血管舒张敏感性差异。有趣的是，我们的初步数据表明，H2S以内皮依赖性方式扩张了小（电阻）动脉大动脉无效的浓度。但是，耗尽EC膜胆固醇动脉揭示了H2S介导的血管舒张，表明膜脂质含量和结构域调节H2S 信号。此外，我们的初步数据表明，本机EC胆固醇含量在大动脉中比电阻动脉。 EC膜胆固醇含量介导的先天区域差异的概念介导 EC扩张的功能差异是完全新颖的，我们的初步数据（图6）证明了这可能是通过ATP结合盒家族A1（ABCA1）和磷脂转移引起的胆固醇外排升高引起蛋白质（PLTP）。重要的是，我们以前已经表明，EC膜胆固醇的变化似乎导致疾病功能障碍。因此，EC膜胆固醇是一个重要但未经过调查的血管功能的变量。该项目的总体目标是两个方面。首先，阐明机制领先对于我们在EC膜胆固醇含量中观察到的功能显着差异和小动脉。第二个是在体外和体内定义方式，即EC膜中的这些差异胆固醇控制EC功能，特别是H2S诱导的扩张。因此，我们假设这是增强的电阻动脉EC中的胆固醇外流增强了下游H2S信号传导目标1：确定导致异质膜胆固醇含量的机制大小动脉。目标2：确定膜胆固醇调节EC中H2S信号的机制。完成拟议的研究将通过阐明H2S扩张的调节来填补现有的知识差距确定小动脉和大动脉之间的EC功能差异。从概念上讲，该项目非常创新侧重于膜胆固醇运输的新型能力，充当血管舒张的调节剂。这项工作将提高我们对EC的基本特性的理解，从而极大地影响我们的理解血压调节和局部血流控制，并可能识别出治疗的药物靶标多种血管驱动疾病。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面