Carbon monoxide and vascular cell function

描述(由申请人提供)：这项提议的广泛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)作为一种生物重要气体，促进动脉损伤后的动态平衡。我们最近证实，HO-1的基因转移或外源性CO抑制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显著减少有关。我们现在建议扩展这些研究，并建立CO调节动脉损伤和血管疾病后内皮细胞(EC)功能的意义和机制。这一建议的中心假设是，一氧化碳在动脉损伤后促进血管内皮细胞生长方面发挥关键作用，并且一氧化碳逆转高同型半胱氨酸血症和糖尿病的内皮功能障碍。我们进一步认为，CO通过激活eNOS来介导这些效应。在目标1中，我们将研究内源性或外源性一氧化碳在调节血管内皮细胞功能和动脉损伤后再生长中的作用。这些研究将探讨一氧化碳对内皮细胞增殖、迁移、凋亡和衰老的影响，并确定eNOS介导的NO释放是否参与了一氧化碳的生物学作用。我们还将研究CO调节eNOS活性的机制，探索可能的转录、转录后和翻译后调控模式。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合成的诱导是否以一种适应性的方式发挥功能，以保护内皮功能和血压。在目标3中，我们将调查糖尿病患者一氧化碳合成的失调是否有助于内皮功能障碍的发展。此外，我们将研究内源性一氧化碳合成的恢复或外源性一氧化碳的输送是否能纠正动脉损伤后的内皮功能和再生。预计这些研究将建立HO-1/CO系统作为EC功能的关键调节因子，并将CO确定为预防内皮功能障碍和血管疾病的一种新的治疗方式。

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.