Regulation of H2S signaling in vascular function

项目总监/首席调查员(最后、第一、中间)：奈克、周、S 内皮细胞功能受损是全身性心血管疾病的首要指标之一。欧共体 功能障碍损害局部器官血流调节，是大多数终末器官损害的主要原因 心血管疾病。内皮细胞还合成一氧化碳和硫化氢的发现 除一氧化氮(NO)外，引起血管扩张的硫化氢(H2S)在内皮细胞中开启了新的篇章 气体传输器生物学。虽然越来越多的证据支持硫化氢在心血管动态平衡中的关键作用， 先前研究中不同的发现在调节和意义上留下了很大的空白。 血管系统中的硫化氢信号。最近，我们发现了一种新的硫化氢信号调节因子，它可以导致深刻的 循环的第一段和第三段之间血管扩张敏感性的差异。有趣的是，我们的 初步数据显示，硫化氢以内皮依赖的方式扩张小(阻力)动脉。 在大动脉中不起作用的浓度。然而，大量消耗EC膜胆固醇 动脉揭示了硫化氢介导的血管扩张，提示膜脂含量和结构域调节硫化氢 发信号。此外，我们的初步数据显示，大动脉中天然EC胆固醇的含量高于 阻力动脉。EC膜胆固醇含量的先天区域差异起中介作用 内皮细胞扩张的功能差异是全新的，我们的初步数据(图6)表明这可能是 由通过ATP结合盒A1家族(ABCA1)和磷脂转移增加的胆固醇外流引起的 蛋白质(Pltp)。重要的是，我们之前已经表明，EC膜胆固醇的变化似乎 导致疾病中的功能障碍。因此，EC膜胆固醇是一种重要的但尚未被研究的 血管功能多变的。这个项目的总体目标是双重的。第一，阐明领导机制 对于我们观察到的EC膜胆固醇含量在功能上的显著差异， 和细小的动脉。二是明确了在体外和体内这些差异在EC膜上的方式 胆固醇控制血管内皮细胞的功能，特别是H_2S诱导的扩张。因此，我们假设增加了 阻力动脉内皮细胞胆固醇流出增强下游H_2S信号 目的1：确定(S)导致膜胆固醇含量不均的机制 大大小小的动脉。 目的2：探讨膜胆固醇调节内皮细胞硫化氢信号转导的机制(S)。 完成拟议的研究将通过阐明硫化氢膨胀的调节来填补现有的知识空白 目的：研究大、小动脉血管内皮细胞功能的差异。从概念上讲，这个项目非常有创新性 它的重点是膜胆固醇运输作为血管扩张调节器的新能力。这部作品 将增加我们对电子商务基本属性的理解，对我们的理解产生重大影响 血压调节和局部血流控制，并可能确定治疗高血压的药物靶点 多种血管驱动的疾病。 OMB编号0925-0001/0002(批准的第03/2020版至2023年2月28日)续页格式页

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