Egr-1, PKC Beta, Signalling and Atherosclerosis

Egr-1、PKC Beta、信号传导和动脉粥样硬化

• 批准号: 7006966
• 负责人: SHI FANG YAN
• 金额: $ 35.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006966
• 关键词: Egr; PKC; Beta; Signalling; Atherosclerosis

DESCRIPTION (provided by applicant): The immediate early gene, early growth response-1 (egr-1), is linked to maladaptive host response mechanisms m settings of acute cellular perturbation. In addition to acute stress, up regulation of egr-1 may be linked to chronic vascular stress. Transcripts for egr-1 were up regulated in both human and murine atherosclerotic lesions compared to adjacent non-atheromatous plaque, thereby suggesting that the impact of egr-1 in vascular stress might not be limited to the acute setting, rather that egr-1 might impact on chronic vascular perturbation, such as atherosclerosis. Our preliminary studies support this concept, as real time PCR revealed a time-dependent .increase in egr-1 transcripts in aortae of apo E (0) mice versus C57BL/6 controls at ages 6, 8, 10, 14 & 24 weeks. Immunohistochemistry demonstrated that the principal egr-1 expressing cells in atheromata were mononuclear phagocytes (MP) and smooth muscle cells (SMC). Homozygous egr-1 (0) mice in the apolipoprotein E (apo E) (0) background displayed significantly reduced atherosclerosis at the aortic root compared with apo E (0) animals at 14 or 24 weeks of age. In parallel, transcripts for proinflammatory & procoagulant mediators such as JE/MCP- 1, IL-1beta, VCAM-1, ICAM-1, tissue factor (TF) and PAI-1 were significantly diminished in double (0) mice versus mice solely deficient in apo E (0). To test if the PKCbeta axis, a key upstream regulator of egr-1 in acute hypoxia, modulated regulation of egr-1 in chronic vascular stress, we bred homozygous PKCbeta (0) mice into the apo E (0) background. A striking decrease in atherosclerotic lesion area was evident at age 24 weeks in PKCbeta (0)/apo E (0) vs apo E (0) mice. Levels of plasma glucose and cholesterol/triglyceride did not differ between egr- 1 (0)- or PKCbeta (0)/apo E (0) mice versus apo E (0) animals, thus implicating egr-1 and PKCbeta as distinct facets in atherosclerosis. We hypothesize that PKCbeta-dependent up regulation of egr-1 contributes importantly to acceleration of proinflammatory and prothrombotic mechanisms in the vessel wall; processes linked to the pathogenesis of atherosclerosis. We propose to dissect the biochemical and signaling mechanisms by which PKCbeta and egr-1 contribute to lesion development/progression in hypercholesterolemic apo E (0) mice and anticipate that elucidation of the mechanisms by which these factors impact on atherogenesis may highlight new targets for therapeutic intervention.

描述（由申请人提供）：立即早期基因，早期生长反应-1（egr-1），与急性细胞扰动环境中的适应不良宿主反应机制有关。除了急性应激外，egr-1 的上调可能与慢性血管应激有关。与邻近的非动脉粥样硬化斑块相比，egr-1 的转录本在人类和小鼠动脉粥样硬化病变中均上调，因此表明 egr-1 对血管应激的影响可能不仅限于急性环境，相反，egr-1 可能对慢性血管紊乱的影响，例如动脉粥样硬化。我们的初步研究支持了这一概念，因为实时 PCR 显示，在 6、8、10、14 和 24 周龄时，与 C57BL/6 对照相比，apo E (0) 小鼠主动脉中的 egr-1 转录物存在时间依赖性增加。免疫组织化学表明，动脉粥样硬化斑块中表达egr-1的主要细胞是单核吞噬细胞（MP）和平滑肌细胞（SMC）。 14 或 24 周龄时，与 apo E (0) 动物相比，载脂蛋白 E (apo E) (0) 背景中的纯合 egr-1 (0) 小鼠主动脉根部动脉粥样硬化显着减少。与此同时，双 (0) 小鼠中促炎和促凝血介质（如 JE/MCP-1、IL-1beta、VCAM-1、ICAM-1、组织因子 (TF) 和 PAI-1）的转录本与单独小鼠相比显着减少缺乏 apo E (0)。为了测试 PKCbeta 轴（急性缺氧时 egr-1 的关键上游调节因子）是否在慢性血管应激中调节 egr-1，我们将纯合 PKCbeta (0) 小鼠培育到 apo E (0) 背景中。与 apo E (0) 小鼠相比，PKCbeta (0)/apo E (0) 小鼠在 24 周龄时动脉粥样硬化病变面积明显减少。血浆葡萄糖和胆固醇/甘油三酯水平在egr-1 (0)-或PKCbeta (0)/apo E (0)小鼠与apo E (0)动物之间没有差异，因此暗示egr-1和PKCbeta作为不同的方面动脉粥样硬化。我们假设 PKCbeta 依赖性的 egr-1 上调对加速血管壁促炎和促血栓形成机制有重要贡献；与动脉粥样硬化发病机制相关的过程。我们建议剖析 PKCbeta 和 egr-1 促进高胆固醇血症 apo E (0) 小鼠病变发展/进展的生化和信号传导机制，并预计阐明这些因素影响动脉粥样硬化形成的机制可能会突出治疗的新靶点干涉。