Role of cytoglobin in promoting smooth muscle cell survival during maladaptive vascular remodeling

细胞珠蛋白在适应不良血管重塑过程中促进平滑肌细胞存活的作用

• 批准号: 10225517
• 负责人: DAVID JOURD'HEUIL
• 金额: $ 40.75万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225517
• 关键词: Adult; Apoptosis; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Biological Availability; Blood Vessels; CASP3 gene; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell Death; Cell Lineage; Cell Survival; Cells; Cellular Stress; Consumption; Gene Expression; Genes; Genetic; Globin; Goals; Heme; Hemoglobin; Homologous Gene; Human; Hyperplasia; In Vitro; Inflammation; Knowledge; Laboratories; Link; LoxP-flanked allele; Medial; Mediating; Medical; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Myoglobin; NOS2A gene; Nitric Oxide; Nitric Oxide Synthase; Oxidation-Reduction; Oxygen; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Pre-Clinical Model; Process; Regulation; Rodent; Role; Sampling; Scheme; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Stress; System; Testing; Tissues; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Vasodilator Agents; Work; atherogenesis; biological adaptation to stress; cohort; design; experimental study; improved; in vivo; indexing; innovation; knock-down; metabolomics; mouse model; novel; novel therapeutic intervention; novel therapeutics; oxygen transport; programs; public health relevance; response; sensor; vascular injury

Our knowledge of mechanisms regulating vascular remodeling in atherosclerotic and non- atherosclerotic vasculopathies is still inadequate. This represents an important rate-limiting step to improve or design new therapeutic interventions that may prove beneficial during atherogenesis or in advanced atherosclerotic lesions. In the cardiovascular system, globins including hemoglobin and myoglobin are thought exclusively to transport and store molecular oxygen and regulate nitric oxide bioavailability. However, recent evidence suggests that this model is not complete and mammalian globins such as cytoglobin (CYGB) might have important functions in vascular remodeling that are independent of oxygen storage and transport. We discovered that CYGB is abundantly expressed in medial smooth muscle cells of rodent and human vessels. We have obtained strong preliminary results showing that CYGB inhibits apoptosis during vascular injury in vivo and in vitro and we have generated a floxed mouse line allowing for tissue specific deletion of CYGB. The goal of this proposal is to test the general hypothesis that smooth muscle CYGB combines novel anti-apoptotic and nitric oxide consuming functions that have favorable effects in inhibiting atherosclerotic plaque pathogenesis. In Aim 1, we will test the hypothesis that smooth muscle specific conditional knockdown of CYGB will increase smooth muscle cell apoptosis, with a detrimental loss of smooth muscle cells, and a decrease in indices of plaque stability. We will use novel genetically encoded cell lineage tracing approaches in a mouse model of atherosclerosis combined with targeted conditional deletion of smooth muscle CYGB. In Aim 2, we will establish the contribution of nitric oxide signaling to the function of CYGB in the vasculature and in advanced atherosclerotic plaques through functional and metabolomics characterization combined with nitric oxide synthase (NOS) and CYGB genetic deletion. In Aim 3, we will determine the mechanism of action of CYGB in apoptosis. To this end, we will establish the role of CYGB in regulating the downstream effector of apoptosis caspase-3 through redox- and gene- regulated inhibition of its activation. Finally, we will test the hypothesis that CYGB serves as an NO and O2 sensor to regulate downstream signals. Overall, this work will be guided through studies of human atherosclerotic plaque samples derived from asymptomatic and symptomatic patients. The results derived from the proposed experiments will challenge the current dogma related to mammalian globin functions as simply oxygen transport and nitric oxide handling systems. Ultimately, we hope to delineate novel pro-survival pathways in the vasculature that could be manipulated to mitigate inappropriate vascular remodeling through combined regulation of apoptosis and nitric oxide bio- availability.

我们对动脉粥样硬化和非动脉粥样硬化患者血管重塑调节机制的认识 动脉粥样硬化性血管病的治疗仍然不足。这是重要的限速步骤， 改进或设计新治疗干预，可能在动脉粥样硬化形成过程中或在 晚期动脉粥样硬化病变在心血管系统中，包括血红蛋白和 肌红蛋白被认为专门运输和储存分子氧并调节一氧化氮 生物利用度然而，最近的证据表明，这种模式是不完整的， 球蛋白如细胞球蛋白（CYGB）可能在血管重塑中起重要作用， 独立于氧气的储存和运输。我们发现CYGB在人的大脑中大量表达， 啮齿动物和人类血管的中膜平滑肌细胞。我们已经获得了强有力的初步结果 表明CYGB在体内和体外血管损伤过程中抑制细胞凋亡， 允许CYGB的组织特异性缺失的floxed小鼠系。这项提案的目的是测试 平滑肌CYGB结合新的抗凋亡和一氧化氮的一般假设 具有抑制动脉粥样硬化斑块发病的有利作用。在 目的1，我们将检验平滑肌特异性条件性敲低CYGB将导致CYGB表达减少的假设。 平滑肌细胞凋亡增加，平滑肌细胞的有害损失， 斑块稳定性指数。我们将使用新的遗传编码细胞谱系追踪方法， 动脉粥样硬化小鼠模型结合平滑肌CYGB的靶向条件性缺失。 在目标2中，我们将建立一氧化氮信号传导对CYGB在脑内的功能的贡献。 通过功能组学和代谢组学研究血管和晚期动脉粥样硬化斑块 表征结合一氧化氮合酶（NOS）和CYGB基因缺失。在目标3中，我们 将确定CYGB在细胞凋亡中的作用机制。为此，我们将确立 CYGB通过氧化还原和基因调控凋亡下游效应因子caspase-3 调节抑制其激活。最后，我们将测试CYGB作为NO的假设， O2传感器调节下游信号。总的来说，这项工作将通过对人类的研究来指导。 来自无症状和有症状患者的动脉粥样硬化斑块样品。结果 将挑战目前与哺乳动物珠蛋白有关的教条 作为简单的氧气运输和一氧化氮处理系统。最终，我们希望 描绘了血管系统中的新的促生存途径， 通过细胞凋亡和一氧化氮生物合成的联合调节， 空房的