Cholesterol Metabolism and Angiogenesis: Role of Statins

胆固醇代谢和血管生成：他汀类药物的作用

• 批准号: 6433846
• 负责人: Jonas Bernard Galper
• 金额: $ 24.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6433846
• 关键词: Adenoviridae; HMG coA reductases; SDS polyacrylamide gel electrophoresis; angiogenesis; angiotensin II; atherosclerosis; atherosclerotic plaque; biological signal transduction; cholesterol; clinical research; fibroblast growth factor; focal adhesion kinase; genetically modified animals; growth factor receptors; guanine nucleotide binding protein; guanosinetriphosphatases; hypertension; hypoxia; laboratory mouse; lipid metabolism; oxidoreductase inhibitor; tissue /cell culture; transfection; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant): Abnormalities of lipid metabolism, hypertension and angiogenesis have all been shown to play a role in the development and growth of atherosclerotic plaques. Angiotensin II has been shown to induce hypertension, and atherosclerosis in vivo and VEGF and angiogenesis in vitro. Preliminary data demonstrate that HMGCoA reductase inhibitors interfere with angiogenesis by inhibiting the angiogenic response to VEGF and FGF-2 in animal models for angiogenesis. Furthermore HMGCoA reductase inhibitors inhibit the formation of capillary-like structures by HUVECs cultured on Matrigel and the formation of tubes by human dermal epithelial cells cultured on a collagen gel. Finally they interfere with VEGF stimulated phosphorylation of VEGF receptors and angiotensin II induction of VEGF expression in HUVECs by inhibiting the posttranslational lipidation of a member of the Rho family of GTPases. The applicant will test 3 hypotheses: 1) using adenoviral vectors expressing mutant Rho GTPases, the applicant will test the hypothesis that angiogenesis is inhibited by HMGCoA reductase inhibitors and regulated by a specific member of the Rho family of GTPases; 2) that VEGF signaling is Rho dependent and inhibited by HMGCoA reductase inhibitors and that angiotensin II, FAK and hypoxia each stimulate angiogenesis and potentiate VEGF signaling via an effect on a common Rho dependent downstream kinase which is inhibited by HMGCoA reductase inhibitors and 3) that HMGCoA reductase inhibitors interfere with the expression of VEGF and VEGF receptors and decrease the neovascularization and the size of atherosclerotic plaques in cholesterol fed and angiotensin II treated Apo-E-/- mice. These studies would support the existence of a new relationship between lipid metabolism, growth factor signaling and hypertension which could have important implications for the treatment of atherosclerosis.

描述（由申请人提供）：脂质代谢异常， 高血压和血管生成均已被证明在 动脉粥样硬化斑块的发育和生长。血管紧张素II已被 显示可诱发高血压和体内动脉粥样硬化，并且 VEGF 和 体外血管生成。初步数据表明 HMGCoA 还原酶 抑制剂通过抑制血管生成反应来干扰血管生成 血管生成动物模型中的 VEGF 和 FGF-2。此外，HMGCoA还原酶 抑制剂抑制 HUVEC 毛细血管样结构的形成 基质胶培养及人真皮上皮管形成 在胶原凝胶上培养的细胞。最后它们干扰 VEGF 刺激 VEGF 受体的磷酸化和血管紧张素 II 诱导 VEGF 通过抑制成员的翻译后脂化在 HUVEC 中表达 GTPase 的 Rho 家族。申请人将测试 3 个假设：1) 使用 表达突变型 Rho GTPases 的腺病毒载体，申请人将测试 血管生成被 HMGCoA 还原酶抑制剂抑制的假设 由 GTPases Rho 家族的特定成员调节； 2) 血管内皮生长因子 信号传导是 Rho 依赖性的并被 HMGCoA 还原酶抑制剂抑制 血管紧张素 II、FAK 和缺氧各自刺激血管生成并增强 VEGF 信号传导通过影响常见的 Rho 依赖性下游激酶来实现 被 HMGCoA 还原酶抑制剂抑制，并且 3) HMGCoA 还原酶 抑制剂干扰 VEGF 和 VEGF 受体的表达 减少新血管形成和动脉粥样硬化斑块的大小 胆固醇喂养和血管紧张素 II 治疗的 Apo-E-/- 小鼠。这些研究将 支持脂质代谢与生长之间存在新的关系 因素信号传导和高血压可能具有重要影响 动脉粥样硬化的治疗。