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）：直接的早期基因，早期生长反应1（EGR-1）与适应不良的宿主反应机制有关急性细胞扰动的设置。除了急性应激外，EGR-1的加强可能与慢性血管应激有关。与邻近的非阴性斑块相比，在人和鼠动脉粥样硬化病变中，EGR-1的转录本受到调节，从而表明EGR-1在血管胁迫中的影响可能不限于急性环境，而EGR-1可能会对慢性血管性扰动的影响，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揭示了apo e（0）小鼠主动脉中的EGR-1转录本的时间依赖性。与6、8、10、14和24周之间的C57BL/6对照相比。免疫组织化学表明，动脉瘤中的主要EGR-1表达细胞是单核吞噬细胞（MP）和平滑肌细胞（SMC）。与14或24周龄时的APO E（0）动物相比，载脂蛋白E（Apo e）（Apo e）（0）中的纯合EGR-1（0）小鼠在主动脉根的动脉粥样硬化显着降低。同时，在双（0）小鼠中，促炎和促凝介质的转录物（例如JE/MCP-1，IL-1BETA，VCAM-1，ICAM-1，ICAM-1，TF），组织因子（TF）和PAI-1的转录物在双（0）小鼠中显着减少，而在APO E中仅缺乏小鼠（0）。为了测试急性缺氧中EGR-1的关键上游调节剂PKCBETA轴是否在慢性血管应激中调节EGR-1的调节，我们将纯合PKCBETA（0）小鼠饲养到Apo E（0）背景中。在PKCBETA（0）/apo e（0）vs apo e（0）小鼠中，动脉粥样硬化病变区域的显着降低在24周内显而易见。 Egr-1（0）或PKCBETA（0）/Apo E（0）小鼠与Apo E（0）动物之间的血浆葡萄糖和胆固醇/甘油三酸酯的水平没有差异，从而暗示EGR-1和PKCBETA作为动脉粥样硬化的不同方面。我们假设PKCBETA依赖性EGR-1的调节对血管壁中的促炎和促血栓形成机制的加速有贡献。与动脉粥样硬化的发病机理有关的过程。我们建议剖析PKCBETA和EGR-1通过这种生化和信号传导机制有助于高胆固醇血症apo e（0）小鼠的病变发展/进展，并预测这些因素对这些因素对动脉粥样硬化的影响可能会突出治疗干预的新靶标的机制。