Role of Cytoglobin in Promoting Smooth Muscle Cell Survival During Maladaptive Vascular Remodeling

项目摘要 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壁中的中膜平滑肌细胞。我们获得了强大的 初步结果表明，CYGB抑制体内和体外血管损伤过程中的细胞凋亡。 这项提议的目的是检验平滑肌CYGB结合新的 抗细胞凋亡和一氧化氮消耗功能， 动脉粥样硬化斑块发病机制。在目标1中，我们将检验平滑肌特异性 CYGB的条件性敲低将增加平滑肌细胞凋亡， 平滑肌细胞和斑块稳定性指数降低。我们将使用新的基因 在动脉粥样硬化小鼠模型中的编码细胞谱系追踪方法结合靶向 平滑肌CYGB的条件性缺失。在目标2中，我们将确定氮的贡献 氧化物信号对血管系统和晚期动脉粥样硬化斑块中CYGB功能的影响 通过功能和代谢组学表征。在目标3中，我们将确定 CYGB在细胞凋亡中的作用。为此，我们将确定CYGB在监管 通过氧化还原和基因调控抑制凋亡caspase-3的下游效应物 activation.总之，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只是氧气运输的教条， 一氧化氮处理系统最终，我们希望描绘新的促生存途径， 可以通过联合使用来操纵血管以减轻不适当的血管重塑 调节细胞凋亡和一氧化氮的生物利用度。

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.