CaMKII/MK2 Signaling in Cardiometabolic Disease

2型糖尿病（T2 D）患者的心血管疾病（CVD）显著增加， 综合治疗心脏代谢疾病。PPG的主要目标是阐明常见的 不同细胞类型的机制，有助于心脏代谢疾病。我们的PPG工作表明， 肥胖/胰岛素抵抗和动脉粥样硬化激活肝细胞（HC）中的CaMKII/MK2激酶途径 和巨噬细胞（M β）。在HC中，该途径破坏胰岛素受体信号传导，导致 全身性胰岛素抵抗，也下调组织纤溶酶原激活剂（tPA），在人类中 预示着更高的CVD风险。在多发性硬化症中，该通路通过损害凋亡细胞促进斑块进展， 清除（红细胞增多症）和炎症消退。在与Tall博士的合作中，我们有证据表明 其机制涉及CaMKII介导的LXR β抑制。最后，根据我们与Accili博士的PPG工作， 和Tall，我们提出HC途径，通过诱导高胰岛素血症，放大了损伤的M β途径， 导致致病性心脏代谢反馈循环。在这方面，总体目标是调查 代谢中HC和M β中CaMKII/MK2途径的机制和后果， 动脉粥样硬化，并探讨其治疗潜力。在目标1中，我们将研究M β CaMKII在 在晚期动脉粥样硬化和胰岛素抵抗的放大中。我们假设CaMKII/MK2 M β通路通过损害分辨率和下调LXR β促进晚期动脉粥样硬化， 其损害MerTK介导的红细胞增多症。我们将使用WD喂养的具有骨髓-CaMKII KO的Ldlr-/-小鼠， 具有或不具有其它改变，例如，和塔尔医生一起做骨髓LXR缺失的检查我们也会喂老鼠， 致动脉粥样硬化/致糖尿病饮食，以检验M β CaMKII途径被胰岛素放大的假设 耐药性和髓样-CaMKII KO在这种情况下将具有特别益处。在目标2中，我们将测试 假设肥胖症患者HC中CaMKII/MK2通路的激活至少通过以下途径促进动脉粥样硬化： 两种机制。首先，基于我们与Tall和Accili博士的PPG工作，高胰岛素血症下调了 胰岛素信号转导，升高M β Ca 2 +i，并激活CaMKII（Aim 1）。第二，我们有令人兴奋的新， 体内数据表明，HC中的CaMKII途径抑制循环tPA活性。低tPA是一个风险因素， 人CVD，与T2 D相关，但在动脉粥样硬化中的确切作用尚不清楚。在这种情况下，我们将测试 在目标1中使用的糖尿病Ldlr-/-小鼠中，沉默HC中CaMKII通路的假设将减少 通过抑制目标1中概述的M β途径以及增加tPA来促进动脉粥样硬化。然后， 基于我们最近的出版物，我们将用CaMKII/MK2的特异性抑制剂治疗糖尿病Ldlr-/-小鼠。 探索我们的研究对心脏代谢疾病的潜在治疗意义的途径。 1

The marked increase in cardiovascular disease (CVD) in patients with type 2 diabetes (T2D) demands an integrated approach to cardiometabolic disease. A major goal of the PPG is to elucidate common mechanisms in distinct cell types that contribute to cardiometabolic disease. Our PPG work has shown that obesity/insulin resistance and atherosclerosis activate a CaMKII/MK2 kinase pathway in hepatocytes (HCs) and macrophages (Ms), respectively. In HCs, this pathway disrupts insulin receptor signaling, leading to systemic insulin resistance, and also down-regulates tissue plasminogen activator (tPA), which in humans predicts higher risk of CVD. In Ms, the pathway promotes plaque progression by impairing apoptotic cell clearance (efferocytosis) and inflammation resolution. In work with Dr. Tall, we have evidence that part of the mechanism involves CaMKII-mediated suppression of LXR. Finally, based on our PPG work with Drs. Accili and Tall, we propose that the HC pathway, by inducing hyperinsulinemia, amplifies the lesional M pathway, leading to a pathogenic cardiometabolic feedback loop. In this context, the overall objective is to investigate the mechanisms and consequences of the CaMKII/MK2 pathways in HCs and Ms in metabolism and atherosclerosis and to explore its therapeutic potential. In Aim 1, we will investigate the role of M CaMKII in advanced atherosclerosis and its amplification by insulin resistance. We hypothesize that the CaMKII/MK2 pathway in Ms promotes advanced atherosclerosis by impairing resolution and by down-regulating LXR, which compromises MerTK-mediated efferocytosis. We will use WD-fed Ldlr-/- mice with myeloid-CaMKII KO, with or without other alterations, e.g., deleted myeloid LXR with Dr. Tall. We will also feed the mice an atherogenic/diabetogenic diet to test the hypothesis that the M CaMKII pathway is amplified by insulin resistance and that myeloid-CaMKII KO will have particular benefit in this setting. In Aim 2, we will test the hypothesis that activation of the CaMKII/MK2 pathway in HCs in obesity promotes atherosclerosis by at least two mechanisms. First, based on our PPG work with Drs. Tall and Accili, hyperinsulinemia down-regulates insulin signaling in Ms, elevates M Ca2+i, and activates CaMKII (Aim 1). Second, we have exciting new in vivo data that the CaMKII pathway in HCs suppresses circulating tPA activity. Low tPA is a risk factor for human CVD, with relevance to T2D, but precise role in atherosclerosis is unknown. In this context, we will test the hypothesis that silencing the CaMKII pathway in HCs in the diabetic Ldlr-/- mice used in Aim 1 will lessen advanced atherosclerosis by suppressing the M pathways outlined in Aim 1 and also by increasing tPA. Then, based on our recent publication, we will treat the diabetic Ldlr-/- mice with a specific inhibitor of the CaMKII/MK2 pathway to explore the potential therapeutic implications of our studies for cardiometabolic disease. 1