The UPR and CaMKIIg in Atherosclerosis and Insulin Resistance

肥胖/胰岛素抵抗导致冠状动脉疾病（CAD）风险增加的两个因素 是晚期动脉粥样硬化中巨噬细胞（Mfs）的死亡，这促进了斑块坏死， 衍生性血脂异常在过去的十年里，Pi的实验室已经阐明了 内质网（ER）应激和Mf胰岛素抵抗促进晚期病变Mf死亡和斑块 通过互补机制坏死。我们的机械研究揭示了一个最近的关键概念， 等待体内测试的是，长期的内质网应激通过激活钙- 活化酶，钙/钙调蛋白依赖性蛋白激酶II-g（CaMKIIg）。我们还发现删除 或抑制肥胖小鼠的肝脏CaMKIIg可防止代谢紊乱，包括 血脂异常因此，一种酶可能对两个互补过程具有关键作用， 胰岛素抵抗受试者中的CAD。因此，本项目的目标是测试Mf CaMKIIg 在Mf胰岛素的小鼠模型中， 抵抗（目的1）和肝脏CaMKIIg缺乏将改善动脉粥样硬化代谢紊乱， 胰岛素抵抗肥胖小鼠（Aim 2）。在目标1中，我们将确定胰岛素中CaMKIIg的沉默是否 耐药Mfs将抑制这些细胞中高水平的ER应激诱导的凋亡，随后进一步 探索保护机制。我们还将检验p-CaMKII（一种测量细胞增殖的方法） 在晚期与早期人类和小鼠动脉粥样硬化中， 病变最重要的是，我们将使用一种独特的小鼠模型来检验高水平的 Mf可减少胰岛素抵抗小鼠中的晚期病变Mf凋亡和斑块坏死， 针对CaMKII缺陷。在目标2中，我们将描述和探索肝脏 肥胖症中的CaMKIIg缺乏改善了肝脏来源的代谢紊乱，包括血脂异常， 然后使用肝脏靶向CaMKIIg缺陷的独特模型来测试体内因果关系。全面完成 通过检验肝脏和Mf CaMKIIg联合缺乏将导致 对胰岛素抵抗小鼠动脉粥样硬化的所有阶段都有显著的有益作用。在这些研究结束时， 我们希望有全面的数据，以确定CaMKIIg作为一个主要的，双重作用的治疗目标， 在肥胖和胰岛素抵抗的情况下预防CAD。 相关性（参见说明）： 肥胖和胰岛素抵抗（IR）是CAD的主要驱动因素。Mf研究集中于斑块坏死， 这是危险的人类斑块的一个关键特征，也是人类IR增加的一个特征。 关于IR患者最重要的系统性CAD风险因素。该项目包括初步数据 并建议使用人体斑块和肝脏标本进行研究。这项工作应该提出新的治疗方法 针对IR受试者动脉壁和肝脏中常见的促动脉粥样硬化途径的策略。

Two factors contributing to the increased risk of coronary artery disease (CAD) in obesity/insulin resistance are death of macrophages (Mfs) in advanced atherosclerosis, which promotes plaque necrosis, and hepatic- derived dyslipidemia. Over the last decade, the Pi's lab has elucidated the mechanisms by which endoplasmic reticulum (ER) stress and Mf insulin resistance promote advanced lesional Mf death and plaque necrosis by complementary mechanisms. A recent key concept revealed by our mechanistic studies, and awaiting in vivo testing, is that prolonged ER stress triggers apoptosis through activation of the calcium- activated enzyme, calcium/calmodulin-dependent protein kinase ll-g (CaMKIIg). We also found that deletion or inhibition of hepatic CaMKIIg in obese mice protected against metabolic disturbances, including dyslipidemia. Thus, one enzyme may have critical effects on two complementary processes that promote CAD in insulin resistant subjects. Thus, the goals of this project are to test the hypotheses that Mf CaMKIIg deficiency will lessen advanced lesional Mf apoptosis and plaque necrosis in a murine model of Mf insulin resistance (Aim 1) and that hepatic CaMKIIg deficiency will improve atherogenic metabolic disturbances in insulin resistant obese mice (Aim 2). In Aim 1, we will determine whether silencing of CaMKIIg in insulin resistant Mfs will suppress the high level of ER stress-induced apoptosis in these cells, followed by further exploration of the mechanisms of protection. We will also test the hypothesis that p-CaMKII, a measure of CaMKII activation, is higher in lesional Mfs in advanced vs. eariier stage human and murine atherosclerotic lesions. Most importantly, we will use a unique mouse model to test the hypothesis that the high level of advanced lesional Mf apoptosis and plaque necrosis in insulin resistant mice will be decreased by Mf- targeted CaMKII deficiency. In Aim 2, we will characterize and explore the mechanisms whereby liver CaMKIIg deficiency in obesity improves the liver-derived metabolic disturbances, including dyslipidemia, and then use a unique model of liver-targeted CaMKIIg deficiency to test causation in vivo. We will complete the link with Aim 1 by testing the hypothesis that combined hepatic and Mf CaMKIIg deficiency will have a marked beneficial effect on all stages of atherosclerosis in insulin resistant mice. At the end of these studies, we hope to have comprehensive data to identify CaMKIIg as a prime, dual-action therapeutic target to prevent CAD in the setting of obesity and insulin resistance. RELEVANCE (See instructions): Obesity and insulin resistance (IR) are major drivers of CAD. The Mf studies are focused on plaque necrosis, a critical feature of dangerous human plaques and one which is increased in human IR. The liver studies focus on the most important systemic CAD risk factors for humans with IR. The project includes preliminary data and proposed studies using human plaque and liver specimens. The work should suggest new therapeutic strategies that target common pro-atherogenic pathways in the arterial wall and liver in IR subjects.