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: 6929817
• 负责人: Jonas Bernard Galper
• 金额: $ 40.5万
• 依托单位: TUFTS MEDICAL CENTER
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929817
• 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（申请人提供）：脂质代谢的异常， 高血压和血管生成都被证明在 动脉粥样硬化斑块的发展和生长。血管紧张素II已经 证明会在体内和VEGF中诱导高血压以及动脉粥样硬化以及 体外血管生成。初步数据表明HMGCOA还原酶 抑制剂通过抑制对血管生成的干扰 动物模型中的VEGF和FGF-2用于血管生成。此外，HMGCOA还原酶 抑制剂抑制HUVEC的形成毛细血管样结构 在Matrigel上培养并通过人真皮上皮形成管 在胶原蛋白凝胶上培养的细胞。最后，它们干扰了刺激的VEGF VEGF受体和血管紧张素II诱导VEGF的磷酸化 通过抑制成员的翻译后脂化在HUVEC中的表达 Rho gtpases家族。申请人将检验3个假设：1） 表达突变体GTPases的腺病毒载体，申请人将测试 HMGCOA还原酶抑制剂和 由Rho gtpases家族的特定成员调节； 2）那个vegf 信号传导依赖于HMGCOA还原酶抑制剂，并抑制 血管紧张素II，FAK和缺氧每个刺激血管生成和增强 VEGF信号通过对常见的RHO依赖性下游激酶的影响 HMGCOA还原酶抑制剂抑制和3）HMGCOA还原酶 抑制剂干扰VEGF和VEGF受体的表达以及 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。这些研究会 支持脂质代谢，生长之间存在新的关系 因子信号和高血压，可能对 动脉粥样硬化的治疗。