CRP, Diabetes, Atherothrombosis

在以前的建议中，中心假设是确定CRP是否通过对两者的影响促进动脉粥样硬化血栓形成。 内皮细胞和单核细胞。我们现在已经实现了这一建议的所有四个目标，并在这一领域取得了进展。 关于CRP对血管的影响总之，我们已经阐明了CRP 抑制eNOS（体外和体内），我们已经记录了Fc-γ受体在 CRP对内皮细胞、巨噬细胞和Wistar大鼠的影响。并进一步阐明了CRP诱导细胞凋亡的机制。 在剪切应力下单核细胞粘附，最后，我们已经证实，在体内，在Wistar大鼠，CRP具有 促进动脉粥样硬化的作用，包括刺激NADPH氧化酶、超氧化物、MPO释放、氧化 LDL摄取、组织因子、巨噬细胞释放MMP-9和降低血管反应性。糖尿病是一种促炎症 以高CRP水平为特征的状态。然而，缺乏数据来研究 CRP在促进糖尿病促炎状态中的作用我们已经用令人兴奋和新颖的初步数据表明， CRP在体内加剧糖尿病环境中的促炎、促氧化作用（自发性糖尿病BB 大鼠）。因此，在这一竞争性更新中，我们希望进一步探索CRP对糖尿病和动脉粥样硬化血栓形成的影响。 为此，我们提出两个具体目标。在具体目标1中，我们将继续扩大我们令人兴奋的 初步发现CRP加重糖尿病BB大鼠的促炎、促氧化状态。在这 模型，我们将确认CRP是否在体内加重糖尿病环境中的促炎、促氧化作用 还阐明了CRP通过使用体内siRNA发挥这些作用的分子机制， 反义寡核苷酸的不同途径鉴定。基于我们小组和其他人的发现， CRP促进促凝表型，在特定目标2中，使用自发性糖尿病BB大鼠，我们将 现在在体内测试CRP对糖尿病环境中血栓形成的影响。此外，我们将通过以下方式阐明机制： 其中CRP在糖尿病状态下促进动脉粥样硬化血栓形成。我们相信这些研究将提供进一步的新数据 为了支持CRP促进体内动脉粥样硬化血栓形成和促凝血、促炎的假设， 糖尿病的表型探讨CRP增强氧化应激的分子机制， 糖尿病环境中的炎症将最终导致靶向减少炎症和氧化应激的治疗。 糖尿病的压力，导致血管病变减少

In the previous proposal, the central hypothesis was to determine if CRP promotes atherothrombosis by effects on both endothelial cells and monocytes. We have now executed all four aims of this proposal and have advanced the field with regards to the vascular effects of CRP. In summary, we have elucidated the molecular mechanism by which CRP inhibits eNOS (in-vitro and in-vivo), we have documented the role of Fc-gamma receptors in the biological effects of CRP on endothelial cells, macrophages and in Wistar rats. Furthermore, we have elucidated the mechanism of CRPinduced monocyte adhesion under shear stress, and finally we have confirmed in-vivo, in Wistar rats, that CRP has effects that promote atherosclerosis including stimulation of NADPH-oxidase, superoxide, MPO release, oxidized LDL uptake, tissue factor, MMP-9 release from macrophages and decreased vasoreactivity. Diabetes is a proinflammatory state that is characterized by high CRP levels. However, there is a paucity of data examining the role of CRP in promoting the pro-inflammatory state in diabetes. We have shown in exciting and novel preliminary data that CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in the diabetic milieu (spontaneously diabetic BB rat). Thus, in this competing renewal, we wish to further explore the effects of CRP on diabetes and atherothrombosis. To this end, we are proposing two specific aims. In specific aim 1, we will continue to expand our exciting preliminary findings that CRP accentuates the pro-inflammatory, pro-oxidant state in the diabetic BB rat. In this model, we will confirm if CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant effects in the diabetic milieu and also elucidate the molecular mechanism (s) by which CRP exerts these effects by employing in-vivo siRNA and antisense oligonucleotides to the different pathways identified. Based on findings largely from our group and others, that CRP promotes a pro-coagulant phenotype, in Specific Aim 2, using the spontaneously diabetic BB rat, we will now test in-vivo the effect of CRP on thrombosis in the diabetic milieu. Also, we will elucidate the mechanism (s) by which CRP promotes atherothrombosis in the diabetic state. We believe these studies will provide further novel data in support of the hypothesis that CRP promotes atherothrombosis in-vivo and a procoagulant, pro-inflammatory phenotype in diabetes. Probing into the molecular mechanisms by which CRP augments oxidative stress and inflammation in the diabetic milieu will eventually lead to therapies targeted at reducing inflammation and oxidative stress in diabetes and resulting in a decrease in vasculopathies