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)：即刻早期基因，早期生长反应-1(EGR-1)，与急性细胞扰动环境中的不适应宿主反应机制有关。除了急性应激，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，人和小鼠动脉粥样硬化病变中EGR-1的转录本上调，从而表明EGR-1在血管应激中的影响可能不仅限于急性环境，而是EGR-1可能影响慢性血管扰动，如动脉粥样硬化。我们的初步研究支持这一概念，因为实时定量PCR显示，在6、8、10、14和24周龄时，载脂蛋白E(0)小鼠主动脉中EGR-1转录水平与C57BL/6对照相比呈时间依赖性增加。免疫组织化学结果显示，动脉粥样硬化中EGR-1的主要表达细胞为单核巨噬细胞(MP)和平滑肌细胞(SMC)。在14或24周龄时，载脂蛋白E(Apo E)(0)背景中的纯合子EGR-1(0)小鼠的主动脉根部动脉粥样硬化显著低于apo E(0)小鼠。与单纯载脂蛋白E(0)缺乏的小鼠相比，双(0)小鼠的促炎和促凝血介质如JE/MCP-1、IL-1β、VCAM-1、ICAM-1、组织因子(TF)和PAI-1的转录显著减少。为了测试PKCβ轴(急性缺氧中EGR-1的关键上游调节因子)是否调节了慢性血管应激中EGR-1的调节，我们将纯合子PKCβ(0)小鼠培育到apo E(0)背景中。24周龄时，PKCβ(0)/apo E(0)组较apo E(0)组动脉粥样硬化斑块面积明显减少。EGR-1(0)或PKC beta(0)/apo E(0)小鼠与apo E(0)小鼠相比，血糖和胆固醇/甘油三酯水平没有差异，因此，EGR-1和PKCβ是动脉粥样硬化的不同方面。我们假设PKCβ依赖的EGR-1上调有助于加速血管壁的促炎和促血栓形成机制，这些过程与动脉粥样硬化的发病机制有关。我们建议剖析PKCβ和EGR-1参与高胆固醇血症载脂蛋白E(0)小鼠病变发生/进展的生化和信号机制，并预期阐明这些因素影响动脉粥样硬化形成的机制可能为治疗干预提供新的靶点。