Carbon monoxide and vascular cell function

描述（由申请人提供）：该提案的广泛长期目标是将血红素加氧酶-1（HO-1）衍生的一氧化碳（CO）确定为促进动脉损伤后体内平衡的生物学重要气体。我们最近证实HO-1的基因转移或外源性一氧化碳给药可阻断动脉损伤后新生内膜的形成，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，并建立的意义和机制，CO调节内皮细胞（EC）的功能，动脉损伤和血管疾病。该建议的中心假设是，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中的内皮功能障碍。我们进一步提出CO通过激活eNOS介导这些效应。在目标1中，我们将研究内源性或外源性一氧化碳对动脉损伤后EC功能和再生的调节作用。这些研究将探讨EC增殖，迁移，凋亡和衰老的影响，并确定是否eNOS介导的NO释放有助于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，转录后和翻译后的调节模式。此外，我们还将研究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。在目标2中，我们将确定高同型半胱氨酸血症中HO-1和CO合成的诱导是否以适应性方式发挥作用，以保护内皮功能和血压。在目标3中，我们将研究糖尿病中CO合成的失调是否有助于内皮功能障碍的发展。此外，我们将研究内源性CO合成的恢复或外源性CO的输送是否纠正动脉损伤后的内皮功能和再生。预计这些研究将确立HO-1/CO系统作为EC功能的关键调节剂，并将确定CO作为预防内皮功能障碍和血管疾病的新型治疗方式。公共卫生相关性：在美国，心血管疾病和中风比其他任何疾病都夺去更多的生命，花费更多的钱。我们实验室的研究已经确定一氧化碳气体是血流和血压的重要调节剂。该项目将探讨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.