PDGFbeta Receptor Activation Promotes Atheroprotective Changes in SMC Phenotype

PDGFbeta 受体激活促进 SMC 表型的动脉粥样硬化变化

• 批准号: 9303020
• 负责人: Gary K Owens
• 金额: $ 64.71万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303020
• 关键词: Age; Alleles; Anti-Inflammatory Agents; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Cause of Death; Cell Count; Cell Lineage; Cells; Clinical; Collagen; Development; Diet; Event; Extracellular Matrix; Foam Cells; Genes; Genetic; Genomics; Gleevec; Goals; Grant; Hemorrhage; Human; Imatinib; In Vitro; Incidence; Inflammatory; Infusion procedures; Interleukin-1 beta; Intravenous infusion procedures; Knock-out; Knockout Mice; Lead; Lesion; Lesion by Stage; Lipids; Mechanics; Medicine; Mesenchymal; Mitogens; Mus; Muscle Cells; Myocardial Infarction; Myofibroblast; Nature; Necrosis; Pathogenesis; Pharmaceutical Preparations; Pharmacology; Phenotype; Phenylephrine; Play; Probability; Progressive Disease; Receptor Activation; Receptor Signaling; Research; Resolution; Role; Rupture; Signal Pathway; Smooth Muscle Myocytes; Stem cells; Stroke; Tamoxifen; Testing; Thick; Thinness; Vascular Smooth Muscle; Western World; atheroprotective; biomarker panel; cell dedifferentiation; cell type; cytokine; feeding; in vivo; indexing; inhibitor/antagonist; macrophage; migration; neutralizing antibody; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pluripotency; receptor; therapeutic target; transcriptome sequencing; virtual; western diet

Atherosclerosis is a progressive disease that is a leading cause of death in the Western world. Remarkably, despite decades of research, there remain major ambiguities regarding the role of smooth muscle cells (SMC) in lesion pathogenesis, as well as mechanisms that control plaque stability and the probability of plaque rupture with possible myocardial infarction (MI) or stroke. The general dogma is that SMC are primarily involved in late not early stage lesions, and that their primary role is atheroprotective by contributing to formation of a fibrous cap. However, recent Nature Medicine studies by our lab involving simultaneous SMC-specific lineage tracing and knockout (KO) of the stem cell pluripotency genes, Oct4 or Klf4 provided compelling evidence that SMC play a much greater role in lesion pathogenesis than has been generally appreciated. Key findings include our showing that: 1) >80% of SMC-derived cells within advanced lesions of ApoE-/- mice lack detectable expression of typical SMC markers; 2) 30-40% of SMC-derived cells within both advanced mouse and human lesions lack detectable SMC markers and have activated markers of MФs; and 3) SMC can have major beneficial or detrimental effects on lesion pathogenesis depending on the nature of their phenotypic transitions. Thus, there is a critical need to identify factors and mechanisms that promote beneficial changes in SMC phenotype. Studies in this proposal will test the overall hypothesis that PDGFβR-dependent changes in SMC phenotype are atheroprotective and that augmentation of the PDGFβR signaling pathway should be one of the primary therapeutic targets for treating advanced atherosclerosis. This hypothesis will be tested in two specific aims. Aim 1 will test the hypothesis that PDGFβR- dependent transitions in SMC phenotypic play a critical role in the development and progression of atherosclerosis. Aim 1a will extend our initial studies showing that SMC specific conditional PDGFβR KO at 6-8 weeks of age followed by 18 weeks of Western diet (WD) resulted in BCA lesions that were larger but virtually lacking SMC to include rigorous analysis of indices of plaque stability and mechanisms for reductions in SMC number within lesions. Aim 1b will test the hypothesis that SMC-specific conditional KO of PDGFβR results in detrimental transitions in SMC phenotype including increased numbers of SMC-derived Lgals3+ foam cells (SMC-FC) and reduced numbers of SMC derived myofibroblasts (SMC-MF) within the fibrous cap. Aim 2 will test the hypothesis that PDGFβR-signaling pathways confer atheroprotective effects within advanced atherosclerotic lesions at least in part through inducing favorable changes in SMC phenotype. Studies will test how SMC-specific or global genetic or pharmacologic inhibition (Aims 2a-2c) or augmentation (infusion of rPDGF- DD, Aim 2d) of PDGFβR signaling in Western diet fed ApoE-/- mice with advanced atherosclerotic lesions impacts overall lesion pathogenesis, indices of plaque stability, SMC phenotypic transitions, and the incidence of plaque rupture. Results may lead to development of novel therapeutic approaches for reducing late stage clinical complications of atherosclerosis by inducing SMC to undergo beneficial changes in phenotype-function that promote formation of a thicker and mechanically more stable fibrous cap, thus reducing the probability of plaque rupture and a possible MI or stroke.

动脉粥样硬化是一种进行性疾病，在西方世界是导致死亡的主要原因。值得注意的是， 尽管经过了几十年的研究，但关于平滑肌细胞(SMC)的作用仍然存在重大的模糊 在病变发病机制中，以及控制斑块稳定性和斑块破裂概率的机制 可能患有心肌梗塞(MI)或中风。一般的教条是，SMC主要参与晚期 而不是早期病变，它们的主要作用是通过促进纤维的形成来保护动脉粥样硬化 帽子。然而，我们实验室最近进行的涉及SMC特定血统追踪的自然医学研究 和干细胞多潜能基因Oct4或Klf4的敲除(KO)提供了令人信服的证据，表明SMC 在病变发病机制中发挥的作用比人们普遍认识的要大得多。主要发现包括我们的 结果显示：1)ApoE-/-小鼠晚期皮损中80%的SMC来源细胞缺乏可检测到的表达 典型的SMC标志物；2)晚期小鼠和人类病变中30-40%的SMC来源的细胞缺乏 可检测到的SMC标志物和已激活的M-Ф标志物S；以及3)SMC可能具有主要的有益或 对病变发病机制的不利影响取决于其表型转换的性质。因此，有 迫切需要确定促进SMC表型有益变化的因素和机制。在这方面的研究 该提案将检验这一总体假设，即血管内皮生长因子βR依赖的SMC表型变化具有动脉粥样硬化保护作用 血小板衍生生长因子βR信号通路的增强应成为治疗的主要靶点之一 晚期动脉粥样硬化。这一假设将在两个具体目标上得到检验。目标1将检验以下假设：PDGFβR- SMC表型的依赖性转变在动脉粥样硬化的发生和发展中起着关键作用。目标 1A将延长我们的初步研究，表明6-8周龄的SMC特异性条件性PDGFβR KO在18周龄后 几周的西方饮食(WD)导致了更大的BCA病变，但实际上缺乏SMC来进行严格的分析 斑块稳定性指标和斑块内SMC数量减少的机制。目标1b将检验假设 PDGFβR的SMC特异性条件性KO导致SMC表型的有害转变，包括增加 SMC来源的Lgals3+泡沫细胞(SMC-FC)数量和SMC来源的肌成纤维细胞(SMC-MF)数量减少 在纤维帽里。目的2验证血小板衍生生长因子β受体信号通路具有动脉粥样硬化保护作用的假设 在晚期动脉粥样硬化病变中，至少部分通过诱导SMC表型的有利变化。研究 将测试SMC特异性或全局遗传或药物抑制(目标2a-2c)或增强(注入rPDGF- 在西方饮食喂养的晚期动脉粥样硬化病变的ApoE-/-小鼠中，血小板衍生生长因子βR信号的Dd，Aim 2d)全面影响 病变发病机制、斑块稳定性指数、SMC表型转变和斑块破裂发生率。结果 可能导致开发新的治疗方法来减少动脉粥样硬化的晚期临床并发症 通过诱导SMC在表型功能上经历有益的变化，促进形成更厚的和 力学性能更稳定的纤维帽，从而降低斑块破裂和可能的心肌梗死或中风的可能性。