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:
    7494137
  • 负责人:
  • 金额:
    $ 35.22万
  • 依托单位:
  • 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 2012-06-30
  • 项目状态:
    已结题

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(申请人提供):皮肤循环是一个可接近的,具有代表性的血管床,用于活体检查导致血管功能障碍的机制。这一建议是我们之前工作的合乎逻辑的扩展,该工作研究了皮肤血流量控制中与年龄相关的变化背后的神经血管机制。拟议的研究扩展了我们先前的研究,以检查高胆固醇血症(HC)人群中的皮肤血管扩张(VD)信号机制。HC的VD信号受损以氧化应激增加和内皮一氧化氮(NO)丢失为特征,这些事件共同导致了与动脉粥样硬化发病相关的内皮功能障碍。介导内皮NO减少的确切机制尚不清楚。HC可能通过以下途径降低NO水平:1)氧化型低密度脂蛋白诱导血管精氨酸酶活性上调,使一氧化氮合酶底物L-精氨酸(L-精氨酸)优先代谢为L-鸟氨酸和尿素;2)内皮(E)一氧化氮合酶解偶联,eNOS因底物(L-精氨酸)或必需辅因子(四氢生物蝶呤)缺乏而产生超氧化物,从而导致氧化应激增加。此外,氧化低密度脂蛋白诱导的血管精氨酸酶活性增强与动脉粥样硬化的发病机制之间存在联系,其机制是通过增加多胺和Pro前体L-鸟氨酸,从而促进内膜增厚。为此,拟议的研究将使用最先进的活体皮肤特异性技术(局部加热和皮内微透析)结合经典的皮肤活检体外生化分析,系统地探索影响HC受损的NO依赖型皮肤VD的机制。特定的AIMS 1和2将分别从机制上研究精氨酸酶和氧化剂应激在eNOS解偶联的背景下的作用,以阐明与年龄匹配的正常胆固醇血症对照组相比,它们在HC的VD功能障碍中的作用。特异性目标3将通过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来补充目标1和2。特定目标4检查了在他汀类药物干预阿托伐他汀治疗前后,在AIMS 1-3中研究的机制。

项目成果

期刊论文数量(0)
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W. LARRY KENNEY其他文献

W. LARRY KENNEY的其他文献

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{{ truncateString('W. LARRY KENNEY', 18)}}的其他基金

Identification of Critical Thermal Environments for Aged Adults
老年人关键热环境的识别
  • 批准号:
    10161701
  • 财政年份:
    2020
  • 资助金额:
    $ 35.22万
  • 项目类别:
Identification of Critical Thermal Environments for Aged Adults
老年人关键热环境的识别
  • 批准号:
    10364699
  • 财政年份:
    2020
  • 资助金额:
    $ 35.22万
  • 项目类别:
Identification of Critical Thermal Environments for Aged Adults
老年人关键热环境的识别
  • 批准号:
    10579937
  • 财政年份:
    2020
  • 资助金额:
    $ 35.22万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    8099649
  • 财政年份:
    2007
  • 资助金额:
    $ 35.22万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7872958
  • 财政年份:
    2007
  • 资助金额:
    $ 35.22万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7296598
  • 财政年份:
    2007
  • 资助金额:
    $ 35.22万
  • 项目类别:
Hypercholesterolemia and Human Skin Blood Flow
高胆固醇血症与人体皮肤血流
  • 批准号:
    7642495
  • 财政年份:
    2007
  • 资助金额:
    $ 35.22万
  • 项目类别:
EFFECT OF HYDRATION STATUS ON BASKETBALL PERFORMANCE: 12-15 YEAR-OLD BOYS
水分状态对篮球表现的影响:12-15 岁男孩
  • 批准号:
    7378538
  • 财政年份:
    2006
  • 资助金额:
    $ 35.22万
  • 项目类别:
EFFECT OF HYDRATION STATUS ON BASKETBALL PERFORMANCE: 16-30 YEAR-OLD MEN
水分状态对篮球表现的影响:16-30 岁男性
  • 批准号:
    7378533
  • 财政年份:
    2006
  • 资助金额:
    $ 35.22万
  • 项目类别:
AGE AND CONTROL OF HUMAN SKIN BLOOD FLOW:: SKIN SYMPATHETIC NERVE ACTIVITY
人类皮肤血流的年龄和控制:: 皮肤交感神经活动
  • 批准号:
    7378532
  • 财政年份:
    2006
  • 资助金额:
    $ 35.22万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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