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

平滑肌细胞胰岛素抵抗和全身代谢功能障碍在动脉粥样硬化发展和晚期病变发病机制中的作用

• 批准号: 10731723
• 负责人: Gary K Owens
• 金额: $ 80.18万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731723
• 关键词: Acceleration; Address; Antibodies; Aorta; Arterial Fatty Streak; Atherosclerosis; Black race; Blood Glucose; Cardiovascular Diseases; Cardiovascular system; Carotid Endarterectomy; Cause of Death; Cd68; Cell Differentiation process; Cell Lineage; Cells; Characteristics; Cholesterol; Collagen; Development; Diabetes Mellitus; Dose; Down-Regulation; Endothelial Cells; Event; Female; Foam Cells; Genes; Genomics; Glucose; Goals; Grant; Hemorrhage; High Prevalence; Histologic; Human; Hyperglycemia; Hyperlipidemia; IRS2 gene; Immune; Impairment; Incidence; Individual; Inflammatory; Injury; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Interleukin-1 beta; Investments; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Lesion; Lesion by Stage; Life Style Modification; Lipids; Macrophage; Maintenance; Mechanics; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Mus; Myocardial Infarction; Myofibroblast; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity Epidemic; PTPN6 gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Proteins; Receptor Signaling; Resistance; Role; Rupture; Sampling; Scaffolding Protein; Signal Transduction; Smooth Muscle Myocytes; Stains; Streptozocin; Stroke; Sudan; Testing; Thick; Thinness; Triglycerides; Woman; aerobic glycolysis; cell type; cytokine; diabetic; diabetic patient; early onset; end stage disease; femoral artery; glucose uptake; human female; indexing; insulin receptor substrate 1 protein; insulin secretion; interest; male; men; mortality; multiplexed imaging; novel; novel therapeutic intervention; sex; validation studies

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.

尽管动脉粥样硬化是美国乃至全球心肌梗塞 (MI) 或中风导致死亡的主要原因。 他汀类药物治疗可降低低密度脂蛋白胆固醇，由于全球肥胖、代谢性疾病的流行，其发病率呈上升趋势 事实上，超过一半的 T2D 死亡率是由糖尿病引起的。 人体组织病理学研究表明，病变部位容易发生斑块破裂。 灾难性血栓栓塞事件，如 MI 或中风，具有薄纤维帽和高 CD68+/ACTA2+ [推测 MФ/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。 然而，我们对其机制了解甚少。 T2D-MetS 中的胰岛素抵抗、高血糖和其他代谢异常会加剧动脉粥样硬化 我们最近证明，尽管多种细胞类型有助于 ACTA2+ 纤维的形成。 cap，长期斑块稳定性依赖于 SMC。此外，我们发现有氧糖酵解是一种途径。 T2D 中的失调是 SMC 转变为对形成至关重要的有益肌成纤维细胞 (MF) 样状态所必需的 克莱蒙斯及其同事的研究结果引起了人们的主要兴趣。 显示 SMC 选择性敲除胰岛素受体底物 1 (IRS1)，胰岛素和胰岛素所需的蛋白质 像生长因子-1 (IGF1) 信号传导一样，导致 SMC 去分化、过度增殖和增加 然而，他们没有进行动脉粥样硬化研究，也没有考虑股动脉损伤后的新内膜形成。 去分化的 SMC 可能对病变发病机制产生有益或有害的影响，具体取决于 本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，包括严重高血糖和高脂血症 与 T2D-MetD 相关的 T2D-MetD 会导致 SMC 表型的痛苦（斑块不稳定）变化。 确定 SMC 中的胰岛素-IGF1 信号传导是否需要其投资于纤维帽并过渡到 斑块稳定 MF 表型将确定整体胰岛素抵抗和相关代谢。 包括高血糖在内的变化，促进动脉粥样硬化的发展和晚期病变的发病机制 诱导 SMC 表型的恶心变化将确定受损的潜在机制。 SMC 中的胰岛素-IGF1 信号传导有助于 T2D/MetS 人类的晚期病变发病机制。 包括：1) 使用我们的新型 SMC 谱系追踪动脉粥样硬化小鼠，并使用全局或 SMC 特异性胰岛素 伴有或不伴有全身代谢功能障碍（包括高血糖和高脂血症）的抵抗力； 严格分析斑块稳定性指标以及SMC和其他病变细胞的表型转变； 基因组研究以确定基因和通路，从而促进 T2D-MetS 斑块不稳定的变化 SMC 表型；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。 用于促进 T2D-MetS 患者斑块稳定性的增加。