Role of Metabolic Reprogramming in Formation and Maintenance of the Acta2+ Atherosclerotic Lesion Protective Fibrous Cap

代谢重编程在 Acta2 动脉粥样硬化病变保护性纤维帽形成和维持中的作用

• 批准号: 10441555
• 负责人: Gary K Owens
• 金额: $ 67.28万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441555
• 关键词: Accounting; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Carotid Endarterectomy; Cause of Death; Cell Lineage; Cells; Cessation of life; Clinical; Clinical Research; Collagen; Coronary artery; Coronary heart disease; Cytoskeleton; Data; Databases; Development; Diet; Endothelial Cells; Endothelium; Energy Metabolism; Energy Metabolism Pathway; Event; Exhibits; Extracellular Matrix; Failure; Flow Cytometry; Genetic; Glucose; Glutamine; Goals; Histologic; Human; In Vitro; Individual; Inflammation; Investigation; Investments; Knock-out; Lactate Dehydrogenase; Lead; Lesion; Lesion by Stage; Life Style Modification; Lipids; Maintenance; Manuscripts; Mechanics; Medicine; Mesenchymal; Metabolic; Microscopic; Modeling; Mus; Myocardial Infarction; Myofibroblast; Nature; Paper; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Play; Probability; Property; Research; Role; Rupture; Sampling; Smooth Muscle Myocytes; Stroke; Testing; Thick; Transforming Growth Factor beta; United States; aerobic glycolysis; antagonist; aortic arch; atherothrombosis; cell type; chronic inflammatory disease; conditional knockout; dietary; dietary approach; feeding; high risk; in vivo; indexing; inhibitor; insight; knock-down; macrophage; metabolic profile; multiplexed imaging; novel; novel strategies; prevent; pyruvate dehydrogenase; response; sex; small hairpin RNA; thrombotic; transcriptome sequencing; transcriptomics; validation studies; western diet

Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain poorly understood. Recent studies from our lab showed that smooth muscle cell (SMC) conditional knockout of the platelet-derived growth factor receptor-β (PdgfrbSMC-Δ/Δ) in ApoE-/- mice was associated with nearly complete failure of SMC to invest into lesions or the fibrous cap. However, surprisingly we observed no changes in lesion size or indices of plaque stability, including the thickness of the Acta2+ fibrous cap, following 18 weeks of Western diet (WD) feeding. Further investigation provided novel insights regarding the mechanisms underlying these changes. Key findings included: 1) contrary to long-standing dogma that Acta2+ fibrous cap cells are derived almost exclusively from SMC, we showed that they account for only 60-70% of Acta2+ cells in advanced ApoE-/- brachiocephalic (BCA) or human coronary artery lesions with the remainder coming from endothelial cell-to-mesenchymal-to-myofibroblast transitions (EndoMT-MFT, 20-25%) and macrophage-to-myofibroblast transitions (MMFT), 10-15%) respectively; 2) loss of SMC investment into lesions with SMC PDGFRB KO was associated with large adaptive increases in EndoMT-MFT and MMFT; 3) increased EndoMT-MFT, and MMFT did not sustain indices of stability when WD feeding was extended to 26 weeks suggesting there may be qualitative differences in Acta2+ fibrous cap cells depending on their origin; 4) RNA-seq analysis on the BCA of 18-week WD-fed PdgfrbSMC-Δ/Δ ApoE-/- mice versus control littermate mice showed that energy metabolism pathways were the top ten upregulated pathways suggesting that metabolic reprogramming may be required for SMC-MF, EndoMT-MF, and MMF transitions; and 5) inhibition of aerobic glycolysis in cultured SMC prevented their transition to a MF state following treatment with PDGF and TGFβ. Studies in this proposal will test the hypothesis that SMC, EC, and macrophage adaptive responses for maintaining plaque stability require major shifts in energy metabolism and that the metabolic state of these cells can be manipulated to stimulate beneficial changes in the phenotype of lesion cells and overall increases in plaque stability. Aim 1 will determine if genetic knockout or pharmacologic inhibition of aerobic glycolysis in SMC and EC lineage tracing ApoE-/- mice with advanced atherosclerosis is associated with evidence of reduced plaque stability. Aim 2 will determine if genetic or pharmacologic promotion of aerobic glycolysis in SMC and EC lineage tracing ApoE-/- lineage tracing mice with advanced atherosclerosis is associated with increased plaque stability. Studies for both aims will include human validation studies using scRNAseq and histological data from stable asymptomatic versus unstable symptomatic carotid endarterectomy samples. All studies will assess sex-dependent determinants of late-stage lesion pathogenesis. Taken together, the proposed studies will provide novel insights regarding mechanisms by which metabolic reprogramming of cells contribute to the cellular and extracellular matrix (ECM) composition of the fibrous cap and may lead to development of novel pharmacological and dietary approaches for enhancing plaque stability.

动脉粥样硬化血栓形成是由不稳定的动脉粥样硬化斑块破裂或侵蚀引起的，是导致心脏病的主要原因