CaMKII/MK2 Signaling in Cardiometabolic Disease

2型糖尿病(T2D)患者心血管疾病(CVD)的显著增加要求 心脏代谢性疾病的综合治疗方法。PPG的一个主要目标是阐明共同的 导致心脏代谢性疾病的不同细胞类型的机制。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CaMKII/MK2激酶通路 巨噬细胞(MS)。在HCS中，这一途径扰乱了胰岛素受体信号，导致 系统性胰岛素抵抗，并下调组织纤溶酶原激活物(TPA)，在人类 预示着患心血管疾病的风险更高。在MS中，该途径通过损害凋亡细胞来促进斑块进展 清除(胞泡吞噬)和消炎。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抑制。最后，基于我们与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，放大病变的M途径， 导致致病的心脏代谢反馈环路。在这方面，总体目标是调查 CaMKII/MK2通路在HCS和M中代谢及后果的机制和后果 探讨动脉粥样硬化的治疗潜力。在目标1中，我们将研究MCaMKII的作用 在晚期动脉粥样硬化及其因胰岛素抵抗而放大的过程中。我们假设CAMKII/MK2 M中的途径S通过损害分辨率和下调LXR促进晚期动脉粥样硬化， 这会损害MerTK介导的胞吐作用。我们将使用WD喂养的患有髓系CaMKII KO的Ldlr-/-小鼠， 有或没有其他改变，例如，与Tall博士一起删除了髓系LXR。我们还将给老鼠喂一只 致动脉粥样硬化/糖尿病饮食以验证M钙调素KII途径被胰岛素放大的假说 耐药和髓系-CaMKII KO在这种情况下将有特别的好处。在目标2中，我们将测试 肥胖症患者HCS中CaMKII/MK2通路激活促进动脉粥样硬化的假说 有两种机制。首先，根据我们对Tall博士和Accili博士的PPG研究，高胰岛素血症下调了 MS体内的胰岛素信号，升高M钙离子i，激活CaMK II(目标1)。第二，我们有令人振奋的新进展 活体数据表明，HCS中的CaMKII途径抑制循环中tPA的活性。低tPA是一种风险因素 人类心血管疾病与T2D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AIM 1中使用的糖尿病Ldlr-/-小鼠在HCS中沉默CaMKII途径的假设将减少 通过抑制目标1中概述的M通路和通过增加tPA来促进动脉粥样硬化。然后, 根据我们最近发表的文章，我们将用一种特定的CaMKII/MK2抑制剂来治疗糖尿病Ldlr-/-小鼠 探索我们的心脏代谢性疾病研究的潜在治疗意义。 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