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 在晚期动脉粥样硬化中巨噬细胞(MFS)死亡，促进斑块坏死，以及肝脏- 衍生性血脂异常。在过去的十年里，PI的实验室已经阐明了 内质网应激和MF胰岛素抵抗促进晚期皮损MF死亡和斑块 由互补机制引起的坏死。我们的机械学研究揭示了一个最新的关键概念，以及 等待体内测试的是，长时间的内质网应激通过激活钙离子触发细胞凋亡- 激活的酶，钙/钙调蛋白依赖的蛋白激酶11-g(CaMKIIg)。我们还发现，删除 或抑制肥胖小鼠肝脏CaMKIIg对代谢紊乱的保护作用，包括 血脂异常。因此，一种酶可能在两个互补的过程中起关键作用 胰岛素抵抗患者的冠心病。因此，该项目的目标是测试假设MF CaMKIIg 缺乏胰岛素可减轻MF胰岛素小鼠模型中晚期MF皮损的凋亡和斑块坏死 抵抗(目标1)和肝脏CaMKIIg缺乏将改善动脉粥样硬化的代谢紊乱 胰岛素抵抗肥胖小鼠(目标2)。在目标1中，我们将确定CaMKIIg在胰岛素中的沉默 耐药的MFS将抑制高水平的内质网应激诱导的细胞凋亡，随后进一步 探索保护机制。我们还将测试p-CaMKII的假设，p-CaMKII是 在晚期人类和小鼠动脉粥样硬化的皮损MFS中，CaMKII活性高于早期。 损伤。最重要的是，我们将使用一种独特的老鼠模型来测试这一假设 米非司酮可减少胰岛素抵抗小鼠皮损晚期微血管细胞凋亡和斑块坏死。 针对CaMKII缺乏症。在目标2中，我们将描述和探索肝脏 肥胖中CaMKIIg缺乏可改善肝源性代谢紊乱，包括血脂异常，以及 然后使用一种独特的肝脏靶向CaMKIIg缺乏症模型来测试体内的因果关系。我们将完成 通过检验肝脏和MF CaMKIIg缺乏症合并将有一个 对胰岛素抵抗小鼠动脉粥样硬化的各个阶段均有明显的有益作用。在这些研究结束时， 我们希望有全面的数据来确定CaMKIIg是主要的、双重作用的治疗靶点 预防冠心病在肥胖和胰岛素抵抗方面的设置。 相关性(请参阅说明)： 肥胖和胰岛素抵抗(IR)是冠心病的主要驱动因素。MF的研究主要集中在斑块坏死上， 这是危险的人类斑块的一个重要特征，也是人类IR增加的一个特征。肝脏研究的焦点 对患有胰岛素抵抗的人类最重要的系统性冠心病危险因素。该项目包括初步数据 并建议使用人类斑块和肝脏样本进行研究。这项工作应该会提出新的治疗方法 针对IR受试者动脉壁和肝脏中常见的促动脉粥样硬化通路的策略。

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.