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: 9769294
• 负责人: DAVID JOURD'HEUIL
• 金额: $ 40.5万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769294
• 关键词: Adult; Antioxidants; 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; Gene Expression Regulation; Genes; Globin; Goals; Heme; Hemoglobin; Homologous Gene; Human; Hyperplasia; In Vitro; Inflammation; Injury; Knowledge; Laboratories; Link; Medial; Mediating; Medical; Modeling; Molecular; Molecular Mechanisms of Action; Myoglobin; Nitric Oxide; 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; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Vasodilator Agents; Vasomotor; Work; atherogenesis; biological adaptation to stress; design; improved; in vivo; indexing; innovation; knock-down; metabolomics; mouse model; novel; novel therapeutic intervention; novel therapeutics; oxygen transport; programs; public health relevance; response

Project Summary 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 in the vessel wall of rodent and human vessels. We have obtained strong preliminary results indicating that CYGB inhibits apoptosis during vascular injury in vivo and in vitro. 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. 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. 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 studies 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.

项目摘要 我们对动脉粥样硬化和非动脉粥样硬化性心脏病血管重构调控机制的认识 动脉粥样硬化性血管病变仍然是不够的。这代表着重要的速率限制步骤 改进或设计新的治疗干预措施，在动脉粥样硬化形成期间或在 晚期动脉粥样硬化病变。在心血管系统中，包括血红蛋白和 肌红蛋白被认为只负责运输和储存分子氧，并调节一氧化氮。 生物利用度。然而，最近的证据表明，这种模式并不是完全的和哺乳动物的。 细胞球蛋白(Cygb)等珠蛋白在血管重塑中可能具有重要作用 不依赖于氧气的储存和运输。我们发现，CygB在 啮齿动物和人类血管管壁的中层平滑肌细胞。我们已经获得了强大的 初步结果表明，CygB在体内和体外均能抑制血管损伤过程中的细胞凋亡。 这项提议的目标是检验平滑肌肉细胞色素B结合了新的 抗细胞凋亡和一氧化氮消耗功能，具有良好的抑制作用 动脉粥样硬化斑块的发病机制。在目标1中，我们将检验这一假说 有条件地敲除Cygb会增加平滑肌细胞的凋亡，并造成有害的 而斑块稳定性指数则下降。我们将从基因上使用小说 联合靶向的动脉粥样硬化小鼠模型的编码细胞谱系示踪方法 有条件地删除平滑肌细胞色素Gb。在目标2中，我们将确定硝酸盐的贡献 血管和晚期动脉粥样硬化斑块中细胞色素B功能的氧化信号转导 通过功能和代谢组学鉴定。在目标3中，我们将确定 细胞色素B在细胞凋亡中的作用。为此，我们会确立中心的角色，以规管 氧化还原和基因调控抑制caspase-3的下游效应 激活。总体而言，这项工作将通过对人类动脉粥样硬化斑块样本的研究来指导 来源于无症状和有症状的患者。从拟议研究中得出的结果 将挑战目前有关哺乳动物珠蛋白功能的教条，如简单的氧气运输和 一氧化氮处理系统。最终，我们希望描绘出新的支持生存的途径 血管系统，可以通过联合治疗来减轻不适当的血管重塑 细胞凋亡的调控和一氧化氮的生物利用度。