Role of Smooth Muscle Cell Insulin Resistance and Systemic Metabolic Dysfunction in Atherosclerosis Development and Late Stage Lesion Pathogenesis

在美国和全球范围内，动脉粥样硬化是心肌梗死（MI）或卒中导致的主要死亡原因。尽管 他汀类药物治疗降低LDL胆固醇，其发病率正在上升，由于全球流行的肥胖，代谢 综合征（MetS）和早发2型糖尿病（T2 D）。事实上，超过一半的T2 D死亡率是由以下原因引起的： 心血管并发症人体组织病理学研究表明，病变易发生斑块破裂， 灾难性血栓栓塞事件，如MI或卒中，具有薄的纤维帽和高的CD 68 +/ACTA 2 + [推测 平滑肌细胞/平滑肌细胞（SMC）]细胞比率。这些特征在动脉粥样硬化中发生率较高， 糖尿病患者和女性与男性的病变。然而，我们对这些机制的理解很差， T2 D-MetS中胰岛素抵抗、高血糖症和其它代谢异常加重动脉粥样硬化 疾病我们最近证明，虽然多种细胞类型有助于ACTA 2+纤维的形成， 长期斑块稳定性取决于SMC。此外，我们发现有氧糖酵解，一种途径， T2 D失调是SMC转变为有益的肌成纤维细胞（MF）样状态所必需的， 和维持稳定的纤维帽。结果是主要的利益考虑到研究的克莱蒙斯和同事 表明SMC选择性敲除胰岛素受体底物-1（IRS 1），胰岛素和胰岛素- 类生长因子-1（IGF 1）信号，导致SMC去分化，过度增殖， 股动脉损伤后新生内膜形成。然而，他们没有进行动脉粥样硬化研究，也没有考虑 去分化的SMC可能对病变的发病机制产生有益或有害的影响，这取决于 它们的表型转变的性质。本研究将检验胰岛素-IGF 1抵抗 在SMC中合并代谢异常，包括严重的高血糖和高脂血症 与T2 D-MetD相关的血小板聚集导致SMC表型的有害（斑块去稳定化）变化。目标1将 确定SMC中的胰岛素-IGF 1信号传导是否是它们投资到纤维帽中并过渡到纤维帽所必需的。 斑块稳定MF表型。目标2将确定是否整体胰岛素抵抗和相关的代谢 包括高血糖在内的变化通过以下方式促进动脉粥样硬化的发展和晚期病变的发病机制： 诱导SMC表型的有害变化。目标3将确定受损的潜在机制， SMC中的胰岛素-IGF 1信号传导有助于T2 D/MetS患者的晚期病变发病机制。研究 包括：1）使用我们新SMC谱系，用整体或SMC特异性胰岛素追踪动脉粥样硬化小鼠 具有或不具有包括高血糖症和高脂血症的全身代谢功能障碍的抵抗; 2） 严格分析斑块稳定性和SMC及其他病变细胞表型转变的指标; 3） 基因组研究，以确定基因和途径，T2 D-MetS促进斑块不稳定的变化， SMC表型;和4）人体验证研究。我们的最终目标是确定新的治疗干预措施 促进T2 D-MetS患者斑块稳定性的增加。

Atherosclerosis is a leading cause of death in the USA and globally due to myocardial infarction (MI) or stroke. Despite statin treatment to reduce LDL cholesterol, its incidence is on the rise due to the global epidemic of obesity, metabolic syndrome (MetS), and early onset type-2 diabetes (T2D). Indeed, more than half of the mortality in T2D is caused by cardiovascular complications. Human histopathological studies have shown that lesions prone to plaque rupture, with catastrophic thromboembolic events like MI or stroke, have a thin fibrous cap and a high CD68+/ACTA2+ [presumed MФ/smooth muscle cell (SMC)] cell ratio. These characteristics occur at a higher prevalence in atherosclerotic lesions of diabetics and in women versus men. However, we have a poor understanding of the mechanisms by which insulin resistance, hyperglycemia, and other metabolic abnormalities in T2D-MetS exacerbate atherosclerotic disease. We recently demonstrated that although multiple cell types contribute to formation of the ACTA2+ fibrous cap, long-term plaque stability is dependent on SMC. Moreover, we showed that aerobic glycolysis, a pathway dysregulated in T2D is required for transition of SMC to a beneficial myofibroblast (MF)-like state critical for formation and maintenance of a stable fibrous cap. Results are of major interest given studies of Clemmons and co-workers showing that SMC-selective knockout of insulin receptor substrate-1 (IRS1), a protein required for insulin and insulin- like growth factor-1 (IGF1) signaling, resulted in de-differentiation of SMC, hyper-proliferation, and increased neointimal formation following femoral artery injury. However, they did no atherosclerosis studies and did not consider that de-differentiated SMC could have beneficial or detrimental effects on lesion pathogenesis depending on the nature of their phenotypic transitions. Studies in this proposal will test the hypothesis that insulin-IGF1 resistance in SMC combined with metabolic abnormalities including the profound hyperglycemia and hyperlipidemia associated with T2D-MetD results in detrimental (plaque de-stabilizing) changes in SMC phenotype. Aim 1 will determine if insulin-IGF1 signaling in SMC is required for their investment into the fibrous cap and transition to a plaque stabilizing MF phenotype. Aim 2 will determine if global insulin resistance and the associated metabolic changes, including hyperglycemia, promote atherosclerosis development and late-stage lesion pathogenesis by inducing detrimental changes in SMC phenotype. Aim 3 will determine potential mechanisms by which impaired insulin-IGF1 signaling in SMC contributes to late-stage lesion pathogenesis in humans with T2D/MetS. Studies include: 1) use of our novel SMC lineage tracing atherosclerotic mice with global or SMC-specific insulin resistance with or without systemic metabolic dysfunction including hyperglycemia and hyperlipidemia; 2) rigorous analysis of indices of plaque stability and phenotypic transitions of SMC and other lesion cells; 3) genomic studies to identify genes and pathways whereby T2D-MetS promote plaque-destabilizing changes in SMC phenotype; and 4) human validation studies. Our ultimate goal is to identify novel therapeutic interventions for promoting increased plaque stability in patients with T2D-MetS.