Hydrogen sulfide and vascular remodeling

描述（由申请人提供）：实验证据表明，气体递质硫化氢在心血管系统中起重要作用，特别是在组织缺血时。然而，脉管系统中硫化氢的具体细胞来源、靶点和机制在很大程度上仍然未知。我们的实验室和其他人的研究表明，硫化氢对慢性组织缺血具有保护作用，慢性组织缺血涉及血管重构反应的增加，如血管生成。重要的是，关于硫化氢如何在体内或体外调节缺血性血管重构的机制信息很少。这个应用程序中的数据揭示了一个新的发现：硫化氢来自半胱硫氨酸！-裂解酶（CSE）选择性地增加缺血组织亚硝酸盐还原为NO，介导血管生成活性的增加，包括HIF-1活性和VEGF表达。本提案中的实验将通过内皮细胞CSE依赖的硫化氢生成增加缺血性亚硝酸盐还原为一氧化氮从而增加缺血性血管重塑的假设来确定这些新结果的分子机制。该假设将通过追求三个特定目标进行检验，包括：1)确定内皮细胞CSE表达如何调节缺血性血管重构反应，2)确定硫化氢增加缺血组织中NO生成的机制及其如何调节HIF-1活性和VEGF表达，以及3)确定内皮细胞CSE依赖的硫化氢对糖尿病缺血性血管重构反应的影响。本课题的成功完成将极大地促进该领域对血管系统硫化氢生物学的认识，为硫化氢- no通路相互作用提供明确的机制信息，并为缺血性血管疾病的治疗提供新的途径。

DESCRIPTION (provided by applicant): Experimental evidence is emerging that the gasotransmitter hydrogen sulfide serves an important role in the cardiovascular system especially during tissue ischemia. However, specific cellular sources, targets, and mechanisms of hydrogen sulfide within the vasculature remain largely unknown. Work from our lab and others demonstrate that hydrogen sulfide is protective against chronic tissue ischemia, which involves increased vascular remodeling responses such as angiogenesis. Importantly, very little mechanistic information exists regarding how hydrogen sulfide modulates ischemic vascular remodeling in vivo or in vitro. Data in this application reveals a novel finding that hydrogen sulfide emanating from cystathionine !-lyase (CSE) selectively augments ischemic tissue nitrite reduction to NO that mediates increased angiogenic activity involving HIF-1" activity and VEGF expression. Experiments in this proposal will determine molecular mechanisms for these novel results through the hypothesis that endothelial cell CSE dependent hydrogen sulfide generation augments ischemic nitrite reduction to NO that increases ischemic vascular remodeling. The hypothesis will be examined through the pursuit of three specific aims including: 1) determine how endothelial cell CSE expression regulates ischemic vascular remodeling responses, 2) determine the mechanisms by which hydrogen sulfide increases NO generation in ischemic tissue and how this regulates HIF-1" activity and VEGF expression, and 3) determine the effect of endothelial cell CSE dependent hydrogen sulfide on diabetic ischemic vascular remodeling responses. Successful completion of this project will significantly advance the fields understanding of hydrogen sulfide biology in the vascular system, provide clear mechanistic information on hydrogen sulfide-NO pathway interactions, and identify novel approaches for ischemic vascular disease therapy. PUBLIC HEALTH RELEVANCE: Peripheral ischemic vascular disease (e.g. Peripheral Arterial Disease (PAD) is a chronic disorder associated with reduced blood flow to the extremities, which results in serious complications such as critical limb ischemia, limb amputation and in some cases may lead to death. Individuals with PAD suffer from endothelial cell dysfunction and lack of bioavailable nitric oxide (NO). Moreover, patients with diabetes are also at a greater risk of developing PAD. Work from our laboratory has discovered that hydrogen sulfide selectively increases endothelial cell NO bioavailability through a novel mechanism of nitrite reduction back to NO. Studies in this proposal will identify critical endothelial cell enzymes regulating hydrogen sulfide formation and subsequent NO formation. These results will identify novel molecular targets for potential therapeutic interventions directed at peripheral ischemic vascular disease.