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Mechanisms of Myocardial Infarction-induced insulin resistance

心肌梗死引起的胰岛素抵抗的机制

基本信息

批准号：
10116453
负责人：
Partha Dutta
金额：
$ 51.63万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116453
关键词：
ANXA5 gene Acute myocardial infarction Address Adipose tissue Anti-Inflammatory Agents Apoptosis Apoptotic Applications Grants Arterial Fatty Streak Bone Marrow Cause of Death Cells Colony-Stimulating Factor Receptors Coronary Data Developed Countries Diabetes Mellitus Diet Event Exhibits Flow Cytometry Genetic Glucose Glucose Clamp Glucose Intolerance High Fat Diet Human Hyperglycemia Immunofluorescence Immunologic Inflammatory Insulin Resistance Interleukin-1 Interleukin-1 beta Interleukin-13 Interleukin-4 Interleukin-6 Knowledge Ligation Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Mouse Strains Mus Myelogenous Myeloid Cells Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Organ Parabiosis Patients Phenotype Play Production Propidium Diiodide Recording of previous events Reporting Role Series Source Supplementation TNF gene Tamoxifen Testing Tissue Differentiation Tissues Visceral cytokine drug development experimental study fasting blood glucose level improved inflammatory milieu insulin sensitivity intravital microscopy macrophage monocyte mortality mouse model neutralizing antibody novel therapeutics prevent recruit

项目摘要

Myocardial infarction (MI) is the leading cause of mortality in the USA. Patients develop insulin resistance after acute MI. In a mouse model of MI, we found coronary ligation significantly increased insulin resistance in mice fed with either a chow diet or high fat diet. Recent studies have shown that MI-induced insulin resistance has direct proatherogenic effects at the level of atherosclerotic plaques leading to a series of cellular atherogenic events and plaque progression. But the mechanistic underpinnings of insulin resistance after MI are not explored. We have recently shown that MI increases production of inflammatory monocytes, which can infiltrate visceral adipose tissue (VAT) and differentiate into macrophages. Consistently, our preliminary data revealed that MI-induced insulin resistance was associated with accumulation of CX3CR1+ CCR2+ monocyte-derived macrophages in VAT. We hypothesize that the influx of monocyte-derived macrophages into VAT after MI creates an inflammatory milieu, resulting in insulin resistance. We will test the hypothesis in three specific aims. 1.We will investigate the dynamics of macrophage subsets in VAT after MI. We will use flow cytometry and intravital microscopy to investigate monocyte accumulation in VAT after MI. 2.To test the mechanisms of MI-induced insulin resistance, we will investigate if loss of M-CSF after MI leads to insulin resistance. Our preliminary experiments showed that coronary ligation in mice reduced systemic levels of M-CSF, a cytokine responsible for tissue resident macrophage survival. 3. We will investigate if the accumulation of monocyte-derived macrophages induces insulin resistance after MI using a mouse strain of tamoxifen-inducible CX3CR1. Furthermore, since monocyte-derived VAT macrophages express high levels of IL-1β, we will use IL-1β neutralizing antibody to explore whether it can improve insulin sensitivity. The proposed grant application will further our understanding of mechanisms behind MI-induced insulin resistance and explore new therapeutic avenues.

心肌梗死（MI）是美国死亡的主要原因。患者出现胰岛素抵抗急性心肌梗死后在小鼠心肌梗死模型中，我们发现冠状动脉结扎显著增加了胰岛素抵抗在喂食普通饲料或高脂肪饲料的小鼠中。最近的研究表明MI诱导的胰岛素阻力在动脉粥样硬化斑块水平具有直接的促动脉粥样硬化作用，导致一系列的细胞致动脉粥样硬化事件和斑块进展。但是胰岛素抵抗的机制基础在MI未被探索之后。我们最近发现MI增加了炎症单核细胞的产生，其可渗入内脏脂肪组织（VAT）并分化成巨噬细胞。因此，我们的初步数据显示MI诱导的胰岛素抵抗与CX 3CR 1+的积聚有关 VAT中的CCR 2+单核细胞衍生的巨噬细胞。我们假设单核细胞源性 MI后巨噬细胞转化为VAT产生炎症环境，导致胰岛素抵抗。我们将测试三个具体目标的假设。1.研究巨噬细胞亚群在VAT中的动态变化 MI后。我们将使用流式细胞术和活体显微镜来研究VAT中单核细胞的积聚， MI后。2.为了探讨MI诱导的胰岛素抵抗的机制，我们将研究M-CSF的丢失是否与MI的胰岛素抵抗有关。导致胰岛素抵抗。我们的初步实验表明，小鼠冠状动脉结扎降低全身M-CSF水平，M-CSF是一种负责组织驻留巨噬细胞存活的细胞因子。3.我们将研究MI后单核细胞源性巨噬细胞的积聚是否诱导胰岛素抵抗使用他莫昔芬诱导型CX 3CR 1小鼠品系。此外，由于单一来源的增值税巨噬细胞表达高水平的IL-1β，我们将使用IL-1β中和抗体来探索它是否可以改善胰岛素敏感性。拟议的赠款申请将进一步加深我们对机制的理解背后MI诱导的胰岛素抵抗和探索新的治疗途径。