Cholesterol Metabolism and Angiogenesis: Role of Statins

描述(申请人提供)：脂代谢异常， 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一直是 在体内可诱发高血压和动脉粥样硬化，而血管内皮生长因子和 体外血管生成。初步数据表明，HMGCoA还原酶 抑制物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血管内皮生长因子和成纤维细胞生长因子-2此外，HMGCoA还原酶 抑制剂抑制人脐静脉内皮细胞毛细血管样结构的形成 人真皮上皮细胞在Matrigel上的培养和成管 培养在胶原胶上的细胞。最后，它们干扰刺激的血管内皮生长因子 血管内皮生长因子受体的磷酸化与血管紧张素II对血管内皮生长因子的诱导 通过抑制一个成员的翻译后脂化在人脐静脉内皮细胞中表达 属于Rho家族的GTP酶。申请者将检验3个假设：1)使用 表达突变型Rho GTP酶的腺病毒载体，申请人将测试 假设血管生成被HMGCoA还原酶抑制剂和 受Rho家族GTP酶的特定成员调控；2)血管内皮细胞生长因子 信号转导依赖于Rho，并被HMGCoA还原酶抑制剂和 血管紧张素II、FAK和低氧各自刺激血管生成并增强 通过对常见的Rho依赖的下游激酶的影响来传递血管内皮生长因子信号 被HMGCoA还原酶抑制剂抑制，以及3)HMGCoA还原酶 抑制剂干扰血管内皮细胞生长因子及其受体的表达 减少新生血管和动脉粥样硬化斑块的大小 胆固醇喂养和血管紧张素II治疗载脂蛋白E-/-小鼠。这些研究将 支持脂代谢、生长发育之间存在新的关系 因子信号转导与高血压之间的关系 动脉粥样硬化的治疗。

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.