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，动脉粥样硬化是心肌梗死(MI)或中风的主要死亡原因。尽管 他汀类药物治疗可降低低密度脂蛋白胆固醇，其发病率因肥胖的全球流行而呈上升趋势，代谢 综合征(METS)和早发性2型糖尿病(T2D)。事实上，在T2D中，超过一半的死亡是由 心血管并发症。人类组织病理学研究表明，病变容易发生斑块破裂， 灾难性的血栓栓塞性事件，如心肌梗塞或中风，具有薄的纤维帽和高的CD68/ACTA2[推测 MФ/SMC]细胞比率。这些特征在动脉粥样硬化的高患病率中出现。 糖尿病患者的皮损以及女性与男性之间的差异。然而，我们对其产生的机制了解甚少。 T2D-Met的胰岛素抵抗、高血糖和其他代谢异常加剧动脉粥样硬化 疾病。我们最近证实，尽管多种细胞类型有助于ACTA2纤维状细胞的形成 冠脉粥样硬化斑块的长期稳定性取决于SMC。此外，我们还发现，有氧糖酵解是一种途径 SMC向有益的肌成纤维细胞(MF)样状态转变需要T2D的失调，这是形成的关键 以及保持稳定的纤维帽。由于对克莱蒙斯和同事的研究，研究结果很有意义。 研究表明，SMC选择性敲除胰岛素受体底物-1(IRS1)，这是一种胰岛素和胰岛素所需的蛋白质- 像生长因子-1(IGF1)信号一样，导致SMC去分化、过度增殖和增加 股动脉损伤后新生内膜的形成。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在病变的发病机制中可能有有利的或不利的影响，这取决于 它们的表型转变的性质。这项提案中的研究将检验胰岛素-IGF1抵抗的假设 SMC合并代谢异常，包括重度高血糖和高脂血症 与T2D-MetD相关会导致SMC表型的不利变化(斑块去稳定化)。目标1将 确定是否需要SMC中的胰岛素-IGF1信号使其投资于纤维帽并转变为 斑块稳定的MF表型。目标2将确定全球胰岛素抵抗和相关代谢 变化，包括高血糖，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 引起SMC表型的不利变化。目标3将确定损伤的潜在机制 SMC中的胰岛素-IGF1信号在人类T2D/METS的晚期病变发病机制中起作用。研究 包括：1)使用我们的新型SMC谱系追踪动脉粥样硬化小鼠的全局或SMC特异性胰岛素 抵抗伴或不伴全身性代谢功能障碍，包括高血糖和高脂血症；2) 严格分析SMC和其他病变细胞斑块稳定性和表型转变的指标；3) 基因组研究以确定T2D-Met促进斑块不稳定变化的基因和途径 SMC表型；4)人类验证性研究。我们的最终目标是确定新的治疗干预措施 用于促进T2D-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.