Hypercholesterolemia and Human Skin Blood Flow

高胆固醇血症与人体皮肤血流

• 批准号: 7494137
• 负责人: W. LARRY KENNEY
• 金额: $ 35.22万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7494137
• 关键词: Acute; Affect; Age; Antiatherogenic; Arginine; Arts; Atherosclerosis; Attenuated; Biochemical; Biopsy; Biopsy Specimen; Blood Circulation; Blood Vessels; Blood flow; Cholesterol; Complement; Control Groups; Coupled; Cutaneous; Defect; Development; Environment; Evaluation; Event; Functional disorder; Gene Expression; Heating; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro; Individual; Intervention; Intervention Trial; Investigation; Laboratories; Link; Localized; Mediating; Microdialysis; Modality; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Oxidants; Oxidative Stress; Pathogenesis; Pathology; Pharmacologic Substance; Polyamines; Population; Proline; Protein Isoforms; Proteins; Punch Biopsy; Research; Research Personnel; Role; Signal Transduction; Signaling Molecule; Site; Skin; Stress; Superoxides; Techniques; Therapeutic; Therapeutic Intervention; Up-Regulation; Urea; Vasodilation; Week; Work; age related; arginase; arginine ascorbate; ascorbate; attenuation; cofactor; enzyme activity; hypercholesterolemia; in vivo; oxidized low density lipoprotein; programs; response; tetrahydrobiopterin; vascular bed; vascular smooth muscle cell proliferation

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（由申请方提供）：皮肤循环是一种可接近的代表性血管床，用于体内检查导致血管功能障碍的机制。这一建议是我们以前研究皮肤血流控制中年龄相关变化的神经血管机制的逻辑延伸。拟议的研究扩展了我们以前的研究，以检查高胆固醇血症（HC）人群中的皮肤血管舒张（VD）信号机制。HC导致VD信号传导受损的特征是氧化应激增加以及内皮一氧化氮（NO）的损失;这些事件共同导致与动脉粥样硬化发病机制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。推测HC可通过其降低NO的位点包括：1）氧化低密度脂蛋白（ox-LDL）诱导的血管平滑肌细胞增殖酶活性上调，其优先将常见的NO合酶（NOS）底物L-精氨酸（L-arg）代谢为L-鸟氨酸和尿素，和2）内皮（e）NOS解偶联，其中eNOS通过作为底物（L-arg）的结果产生超氧化物而有助于增加氧化应激或必需辅因子（四氢生物蝶呤）缺乏。此外，ox-LDL诱导的血管平滑肌细胞增殖酶活性增强与动脉粥样硬化的发病机制之间存在机制联系，通过增加多胺和脯氨酸前体L-鸟氨酸，这有助于内膜增厚。为此，拟定的研究将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）结合皮肤活检的经典体外生化分析，系统地探索影响HC受损的NO依赖性皮肤VD的机制。具体目标1和2将分别从机制上检查eNOS解偶联背景下的血管紧张素转换酶和氧化应激的作用，以阐明与年龄匹配的正常胆固醇血症对照组相比，它们对HC VD功能障碍的贡献。具体目标3将通过eNOS和eNOS酶基因表达、酶活性和蛋白浓度的体外生化分析补充目标1和2。具体目标4检查了目标1-3中研究的阿托伐他汀治疗干预前后的机制。