Carbon monoxide and vascular cell function

描述（由申请人提供）：本提案的长期目标是建立血红素加氧酶-1 （HO-1）衍生的一氧化碳（CO）作为促进动脉损伤后体内平衡的重要生物气体。我们最近证明，HO-1的基因转移或外源性CO的给药可阻断动脉损伤后的新内膜形成，这与血管平滑肌细胞生长和胶原沉积的显著减少有关。我们现在建议扩展这些研究，并确定CO在动脉损伤和血管疾病中调节内皮细胞（EC）功能的意义和机制。该提案的中心假设是，CO在动脉损伤后促进EC生长中起关键作用，并且CO逆转高同型半胱氨酸血症和糖尿病患者的内皮功能障碍。我们进一步提出CO通过激活eNOS介导这些作用。在目的1中，我们将研究内源性或外源性CO对动脉损伤后EC功能和再生的调节作用。这些研究将探讨CO对EC增殖、迁移、凋亡和衰老的影响，并确定eNOS介导的NO释放是否有助于CO的生物学作用。我们还将研究CO调节eNOS活性的机制，探索可能的转录、转录后和翻译后调节模式。此外，我们将研究HO-1基因转移、HO-1基因缺失或CO给药对啮齿动物颈动脉损伤后内皮功能和再生的影响。在目的2中，我们将确定在高同型半胱氨酸血症中诱导HO-1和CO合成是否以适应性方式起作用，以保护内皮功能和血压。在目标3中，我们将研究糖尿病CO合成失调是否导致内皮功能障碍的发生。此外，我们将研究内源性一氧化碳合成的恢复或外源性一氧化碳的递送是否能纠正动脉损伤后的内皮功能和再生。预计这些研究将确定HO-1/CO系统作为EC功能的关键调节因子，并将确定CO作为预防内皮功能障碍和血管疾病的新治疗方式。公共卫生相关性：在美利坚合众国，心血管疾病和中风夺去的生命和花费的金钱比任何其他疾病都多。我们实验室的研究已经确定一氧化碳气体是血液流动和血压的关键调节器。该项目将探索低剂量一氧化碳在预防动脉阻塞和治疗高血压方面的可能治疗应用。

DESCRIPTION (provided by applicant): The broad long-term objective of this proposal is to establish heme oxygenase-1 (HO-1)-derived carbon monoxide (CO) as a biologically important gas that promotes homeostasis following arterial injury. We have recently demonstrated that gene transfer of HO-1 or the exogenous administration of CO blocks neointima formation following arterial injury, and that this is associated with a marked decrease in vascular smooth muscle cell growth and collagen deposition. We now propose to extend these studies and establish the significance and mechanism by which CO regulates endothelial cell (EC) function following arterial injury and in vascular disease. The central hypothesis of this proposal is that CO plays a critical role in promoting EC growth following arterial injury and that CO reverses endothelial dysfunction in hyperhomocysteinemia and diabetes. We further propose that CO mediates these effects via the activation of eNOS. In aim 1, we will examine the effect of endogenously derived or exogenously administered CO in regulating EC function and regrowth following arterial injury. These studies will investigate the effect of CO on EC proliferation, migration, apoptosis, and senescence, and determine whether the eNOS-mediated release of NO contributes to the biological actions of CO. We will also examine the mechanism by which CO regulates eNOS activity exploring possible transcriptional, postranscriptional, and posttranslational modes of regulation. In addition, we will investigate the effect of HO-1 gene transfer, HO-1 gene deletion, or CO administration on endothelial function and regrowth following carotid artery injury in rodents. In aim 2, we will determine whether the induction of HO-1 and CO synthesis in hyperhomocysteinemia functions in an adaptive manner to preserve endothelial function and blood pressure. In aim 3, we will investigate whether the dysregulation of CO synthesis in diabetes contributes to the development of endothelial dysfunction. In addition, we will examine whether restoration of endogenous CO synthesis or exogenous delivery of CO corrects endothelial function and regrowth following arterial injury. It is anticipated that these studies will establish the HO-1/CO system as a critical regulator of EC function, and will identify CO as a novel therapeutic modality in preventing endothelial dysfunction and vascular disease. PUBLIC HEALTH RELEVANCE: Cardiovascular disease and stroke claims more lives and costs more money than any other disease in the United States of America. Studies in our laboratory have identified the gas carbon monoxide as a critical regulator of blood flow and blood pressure. This project will explore the possible therapeutic application of low doses of carbon monoxide in preventing the blockage of arteries and in treating high blood pressure.