Epigenetic control of vascular smooth muscle in cardiovascular disease

心血管疾病中血管平滑肌的表观遗传控制

• 批准号: 8761918
• 负责人: Kathleen Ann Martin
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761918
• 关键词: Address; Adenoviruses; Affect; Angioplasty; ApoE knockout mouse; Arterial Injury; Arteriosclerosis; Atherosclerosis; Blood Vessels; Blood flow; Bypass; Cardiac Myocytes; Cardiovascular Diseases; Cell Differentiation process; Cholesterol; Chromatin; Chronic; Consensus Sequence; Contractile Proteins; Data; Diet; Differentiation Inducer; Disease; Disease model; Down-Regulation; Embryo; Epigenetic Process; Exhibits; Failure; Family; Fatty acid glycerol esters; Gel; Gene Expression; Genes; Growth; Growth and Development function; Hematopoietic stem cells; Human; Hyperplasia; Hypertension; In Vitro; Injury; Knock-out; Mediator of activation protein; Methods; Methylation; Minor Histocompatibility Antigens; Modeling; Modification; Molecular Conformation; Mus; Muscle Fibers; O-GlcNAc transferase; Operative Surgical Procedures; Organ Transplantation; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Pluronics; Prevention therapy; Procedures; Property; Protein translocation; Proteins; Publishing; Regulation; Role; Site; Smooth Muscle; Smooth Muscle Myocytes; Stem cells; Subfamily lentivirinae; T-cell acute lymphocytic leukemia 1 protein; Time; Transplantation; Vascular Diseases; Vascular Smooth Muscle; Viral; Work; Wound Healing; base; bisulfite; cardiovascular disorder prevention; chromatin immunoprecipitation; femoral artery; macrophage; mouse model; myocardin; novel; novel therapeutic intervention; overexpression; platelet-derived growth factor BB; pluripotency; prevent; promoter; protein expression; public health relevance; response; transdifferentiation; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Vascular smooth muscle cells (VSMC) exhibit a remarkable plasticity that allows for reversible differentiation and de-differentiation. This propety is distinct from skeletal or cardiac myocytes, which undergo terminal differentiation. Smooth muscle plasticity is important in normal development, growth, and wound healing, but also contributes to pathologies including atherosclerosis, intimal hyperplasia, hypertension, and transplant arteriosclerosis. Because VSMC exhibit this unique plasticity, we hypothesized that regulatory mechanisms found in other types of stem cells might also be involved in VSMC phenotypic modulation. Indeed, our preliminary data demonstrate that de-differentiated VSMC express multiple stem cell genes, including Oct4, Nanog, and KLF4. As the TET (ten-eleven translocation) family of chromatin-modifying proteins has recently been implicated as essential regulators of pluripotency in embryonic and hematopoietic stem cells, we investigated the roles of TET proteins in VSMC. Our preliminary data reveal that TET2 is expressed at high levels in VSMC, and is induced by differentiating agents but repressed by PDGF-BB. We find that TET2 is necessary and sufficient for SMC differentiation, where TET2 associates with contractile gene promoters and increases accessibility, but represses chromatin at stem cell gene promoters. We further found that TET2 is expressed at high levels in normal vessels, but markedly downregulated in disease states, including human atherosclerosis and intimal hyperplasia in mice. Importantly, TET2 overexpression rescues intimal hyperplasia post-arterial injury. We hypothesize that TET2 is a novel epigenetic master regulator of VSMC phenotype. We believe we have uncovered a fundamental new mechanism that is the basis for smooth muscle plasticity. As such, this work has important implications for multiple vascular diseases. In the following specific aims, we propose to address mechanisms of action of TET2, and determine the role of TET2 in vascular disease models. In Specific Aim 1, we will use cutting edge methods to determine the epigenetic mechanisms by which TET2 regulates methylation and gene expression at contractile and stem cell promoters. In Specific Aim 2, we will use mouse models to determine the role of TET2 in the pathogenesis of cardiovascular diseases, including atherosclerosis, intimal hyperplasia, and graft arteriosclerosis. Because we have found that epigenetic regulation by TET2 lies at the apex of VSMC phenotypic modulation, controlling other known mediators such as myocardin, SRF, and KLF4, we propose that understanding the mechanisms of TET2 action at the cellular and disease level will generate new therapeutic approaches for treatment and prevention of cardiovascular disease.

描述（由申请人提供）：血管平滑肌细胞（VSMC）表现出显着的可塑性，允许可逆分化和去分化。这种特性与进行终末分化的骨骼肌细胞或心肌细胞不同。平滑肌可塑性对于正常发育、生长和伤口愈合很重要，但也会导致动脉粥样硬化、内膜增生、高血压和移植动脉硬化等病理学。由于 VSMC 表现出这种独特的可塑性，我们假设其他类型干细胞中发现的调节机制也可能参与 VSMC 表型调节。事实上，我们的初步数据表明，去分化的 VSMC 表达多种干细胞基因，包括 Oct4、Nanog 和 KLF4。由于染色质修饰蛋白 TET（10-11 易位）家族最近被认为是胚胎和造血干细胞多能性的重要调节因子，我们研究了 TET 蛋白在 VSMC 中的作用。我们的初步数据显示，TET2 在 VSMC 中高水平表达，并受分化剂诱导，但受 PDGF-BB 抑制。我们发现 TET2 对于 SMC 分化是必要且充分的，其中 TET2 与收缩基因启动子相关并增加可及性，但抑制干细胞基因启动子处的染色质。我们进一步发现 TET2 在正常血管中高水平表达，但在疾病状态下显着下调，包括人类动脉粥样硬化和小鼠内膜增生。重要的是，TET2 过度表达可以挽救动脉损伤后的内膜增生。我们假设 TET2 是 VSMC 表型的新型表观遗传主调节因子。我们相信我们已经发现了一种基本的新机制，它是平滑肌可塑性的基础。因此，这项工作对多种血管疾病具有重要意义。在以下具体目标中，我们建议解决 TET2 的作用机制，并确定 TET2 在血管疾病模型中的作用。在具体目标 1 中，我们将使用尖端方法来确定 TET2 调节收缩细胞和干细胞启动子处的甲基化和基因表达的表观遗传机制。在具体目标2中，我们将使用小鼠模型来确定TET2在心血管疾病发病机制中的作用，包括动脉粥样硬化、内膜增生和移植物动脉硬化。因为我们发现 TET2 的表观遗传调控位于 VSMC 表型调节的顶点，控制其他已知的介质，如心肌素、SRF 和 KLF4，所以我们建议了解 TET2 在细胞和疾病水平上的作用机制将产生新的治疗方法治疗和预防心血管疾病的方法。