Hypercholesterolemia and Human Skin Blood Flow

高胆固醇血症与人体皮肤血流

基本信息

批准号：
8099649
负责人：
W. LARRY KENNEY
金额：
$ 35.34万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-07 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099649
关键词：
Acute Affect Age Antiatherogenic Arginine Atherosclerosis Attenuated Biochemical Biopsy Biopsy Specimen Blood Circulation Blood Vessels Blood flow Cholesterol Complement Control Groups Coupled Cutaneous Defect Development Environment Event Functional disorder Gene Expression Heating Human Hydroxymethylglutaryl-CoA Reductase Inhibitors In Vitro Individual Intervention Intervention Trial Investigation Laboratories Link Mediating Microdialysis Modality Nitric Oxide Nitric Oxide Synthase Ornithine Oxidative Stress Pathogenesis Pathology Pharmacologic Substance Polyamines Population Proline Protein Isoforms Proteins Punch Biopsy Research Research Personnel Role Signal Transduction Signaling Molecule Site Skin Superoxides Techniques Therapeutic Intervention Up-Regulation Urea Vasodilation Work age related arginase arginine ascorbate ascorbate attenuation cofactor enzyme activity hypercholesterolemia in vitro activity in vivo oxidant stress oxidized low density lipoprotein programs response tetrahydrobiopterin therapeutic evaluation vascular bed vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): The cutaneous circulation is an accessible, representative vascular bed for in vivo examination of mechanisms that contribute to vascular dysfunction. This proposal is a logical extension of our previous work investigating the neurovascular mechanisms underlying age-related changes in the control of skin blood flow. The proposed studies expand our previous research to examine cutaneous vasodilatory (VD) signaling mechanisms in a hypercholesterolemic (HC) population. Impaired VD signaling with HC is characterized by an increase in oxidant stress coupled with the loss of endothelial nitric oxide (NO); together these events contribute to endothelial dysfunction associated with the pathogenesis of atherosclerosis. The precise mechanisms mediating decreased endothelial NO remain unclear. Putative sites through which NO may be decreased with HC include 1) oxidized low density lipoprotein (ox-LDL)-induced upregulation of vascular arginase activity, which preferentially metabolizes the common NO-synthase (NOS) substrate L- arginine (L-arg) to L-ornithine and urea and 2) endothelial (e)NOS uncoupling where eNOS contributes to increased oxidant stress by producing superoxide as a result of substrate (L-arg) or essential cofactor (tetrahydrobiopterin) deficiency. Additionally, there is a mechanistic link between ox-LDL-induced augmented vascular arginase activity and the pathogenesis of atherosclerosis through an increase in the polyamine and proline precursor L-ornithine which contributes to intimal thickening. To this end, the proposed investigations will systematically explore mechanisms affecting impaired NO- dependent cutaneous VD with HC using state-of-the-art in vivo skin specific techniques (local heating and intradermal microdialysis) paired with classic in vitro biochemical analysis of cutaneous biopsies. Specific Aims 1 and 2 will mechanistically examine the roles of arginase, and oxidant stress in the context of eNOS uncoupling, respectively, to clarify their contributions to VD dysfunction with HC compared to an age- matched normocholesterolemic control group. Specific Aim 3 will complement Aims 1 and 2 with in vitro biochemical analysis of eNOS and arginase gene expression, enzyme activity, and protein concentration. Specific Aim 4 examines the mechanisms investigated in Aims 1-3 before and after a statin therapy intervention with atrovastatin.

描述（由申请人提供）：皮肤循环是一种可进入的代表性血管床，用于体内检查导致血管功能障碍的机制。该建议是我们以前研究的逻辑扩展，研究了皮肤血流控制与年龄相关的变化的神经血管机制。拟议的研究扩大了我们先前的研究，以检查高胆固醇（HC）种群中皮肤血管舒张（VD）信号传导机制。使用HC的VD信号受损的特征是氧化应激的增加以及内皮一氧化氮的损失（NO）；这些事件共同导致与动脉粥样硬化的发病机理相关的内皮功能障碍。介导的确切机制降低了内皮，尚不清楚。 Putative sites through which NO may be decreased with HC include 1) oxidized low density lipoprotein (ox-LDL)-induced upregulation of vascular arginase activity, which preferentially metabolizes the common NO-synthase (NOS) substrate L- arginine (L-arg) to L-ornithine and urea and 2) endothelial (e)NOS uncoupling where eNOS contributes to increased oxidant通过底物（L-ARG）或必需辅助因子（四氢生物翅目）缺乏产生超氧化物的压力。此外，通过增加多胺和脯氨酸前体L-雌氨酸的增加，OX-LDL诱导的增强血管精氨酸活性与动脉粥样硬化的发病机理之间存在机械联系，这有助于内膜增厚。为此，提出的研究将系统地探索使用最先进的体内皮肤特异性技术（局部加热和皮内微透析）与经典的体外体外生物化学分析，使用最先进的皮肤特异性技术（局部加热和皮内微透析）使用最先进的皮肤特异性技术（局部加热和皮内微透析），从而系统地探索影响不依赖皮肤VD的机制。具体目的1和2将在机械上检查精氨酸酶的作用，并在eNOS解偶联的背景下与年龄相匹配的差异固化酯对照组相比，分别在eNOS解偶联的背景下阐明了它们对HC的VD功能障碍的贡献。特定的目标3将与eNOS和精氨酸酶基因表达，酶活性和蛋白质浓度的体外生化分析相辅相成。特定目标4检查了在阿特罗伐他汀进行他汀类药物疗法干预之前和之后的目标1-3中研究的机制。