Role of PTEN in Vascular Lesion Formation

PTEN 在血管病变形成中的作用

• 批准号: 7754395
• 负责人: Mary Cm. Weiser-Evans
• 金额: $ 37.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754395
• 关键词: 1-Phosphatidylinositol 3-Kinase; Actins; Affect; Agonist; Alleles; Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Injury; Arterial Intimas; Atherosclerosis; Attenuated; Automobile Driving; Biological Process; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; CD34 gene; Cause of Death; Cell Proliferation; Cell Wall; Cell physiology; Cells; Chemotactic Factors; Coculture Techniques; Data; Development; Down-Regulation; Embryonic Development; Event; Exhibits; Family; Functional disorder; Genetic Recombination; Germ Layers; Growth; Growth Factor; Hand; Heart Diseases; Hyperplasia; ITGAM gene; In Vitro; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Intervention; Knockout Mice; Label; LacZ Genes; Lead; Lesion; Link; Lipids; Maps; Medial; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutant Strains Mice; Nuclear Receptors; PTEN gene; PTEN protein; Paracrine Communication; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Platelet-Derived Growth Factor; Procedures; Process; Production; Protein Dephosphorylation; Protein phosphatase; Publishing; Recruitment Activity; Regulation; Relative (related person); Research Design; Role; Signal Transduction; Smooth Muscle Myocytes; Societies; Specificity; Staging; Stem cells; Stents; System; Techniques; Technology; Testing; Transplantation; Tumor Suppressor Proteins; Up-Regulation; Vascular remodeling; Work; activating transcription factor; autocrine; base; cell growth; cell motility; chemokine; clinically relevant; cytokine; human FRAP1 protein; in vivo; inhibitor/antagonist; injured; migration; monocyte; neointima formation; novel; paracrine; post intervention; progenitor; programs; protective effect; public health relevance; response; response to injury; restenosis; restoration; transcription factor; tumor progression

DESCRIPTION (provided by applicant): Restenosis is characterized by smooth muscle cell (SMC) accumulation in the arterial intima through dedifferentiation, migration, and proliferation of medial-derived SMC. An inflammatory response, characterized by bone marrow-derived and/or circulating inflammatory and progenitor cell recruitment to the injured vessel, also contributes to restenosis. Several chemokines, including MCP-1/JE, SDF-1a, IL-6, and CXCL1/KC, are rapidly induced in SMC following injury and participate in the remodeling process through the recruitment of inflammatory and vascular progenitor cells. Some of these factors have also been shown to directly affect the biological function of the SMC itself placing the SMC as both a mediator and an effector of the injury response. However, the underlying molecular programs activated in SMC in response to injury are not clearly defined. Our previous work indicates SMC-specific PTEN inactivation, a negative regulator of PI3-kinase signaling, is an early trigger driving vascular lesion formation. We generated inducible SMC-specific PTEN mutant mice (PTEN iKO) and found that, compared to controls, PTEN iKO mice exhibit significant reductions of total PTEN in major vessels with accompanying increased phosphoAkt levels and enhanced neointima formation following carotid arterial injury. PTEN-deficient SMC in vitro exhibit an autocrine growth phenotype under basal conditions and express a cytokine/chemokine profile similar to what is observed in SMC following experimental injury. Preliminary data show that PTEN depletion activates the transcription factors, NF?B and HIF-1a; inhibition of NF?B or HIF-1a blocked the upregulation of specific chemokines mediated by PTEN depletion. On the other hand, our preliminary data suggest that activation of the nuclear receptor, PPAR?, in SMC upregulates PTEN, therefore our studies will examine the ability of PPAR? activation to inhibit SMC proliferation and regulate anti-inflammatory responses through the upregulation of SMC PTEN. Overall, our preliminary data provide evidence that an alteration in SMC PTEN signaling serves as a key initiating determinant driving pathological vascular remodeling through the production of a family of chemoattractants that recruit inflammatory/progenitor cells through a paracrine mechanism and promote an autocrine SMC hyperplastic response. Therefore, restoration of SMC PTEN signaling is anticipated to reverse the cascade of events brought on by vascular injury. We will determine the consequences and mechanism of action of PTEN loss on SMC production of progenitor/inflammatory cell mediators in cultured PTEN null SMC and assess the relative contribution of SMC-specific deletion of PTEN in mice on chemokine-induced SMC hyperplasia and recruitment of progenitor and inflammatory cells during neointima formation following experimental vascular injury in Aim One. In Aim Two, we will determine the role of PPAR? agonists on the upregulation of PTEN and biological functions of SMC and determine the role of PTEN regulation in mediating the protective effects of PPAR? agonists against the development of injury-induced vascular remodeling. PUBLIC HEALTH RELEVANCE: Complications of heart disease remain the leading cause of death in Western societies. While angioplasty/stent deployment and graft transplantations have been widely used for the treatment of atherosclerosis, a significant proportion of these procedures fail due to post-procedure restenosis, characterized by significant cell growth and inflammatory responses that lead to vessel blockage. Therefore, a great deal of effort has gone into defining the underlying mechanisms regulating these processes to reduce post-intervention vascular occlusion. Our studies are designed to test the role and mechanisms of action of a protein, PTEN, expressed by vascular cells in actively blocking the expression of a family of chemokines that otherwise promote vascular cell growth and an inflammatory response following vascular interventions.

描述（由申请人提供）：再狭窄的特征是平滑肌细胞（SMC）通过内侧来源的 SMC 去分化、迁移和增殖而在动脉内膜中积聚。以骨髓来源和/或循环炎症和祖细胞募集到受损血管为特征的炎症反应也会导致再狭窄。几种趋化因子，包括 MCP-1/JE、SDF-1a、IL-6 和 CXCL1/KC，在损伤后在 SMC 中迅速诱导，并通过募集炎症和血管祖细胞参与重塑过程。其中一些因素也已被证明直接影响 SMC 本身的生物学功能，使 SMC 既作为损伤反应的介质又作为损伤反应的效应器。然而，SMC 响应损伤而激活的潜在分子程序尚不清楚。我们之前的工作表明 SMC 特异性 PTEN 失活（PI3 激酶信号传导的负调节因子）是驱动血管病变形成的早期触发因素。我们生成了可诱导的 SMC 特异性 PTEN 突变小鼠 (PTEN iKO)，发现与对照组相比，PTEN iKO 小鼠表现出主要血管中总 PTEN 的显着减少，伴随着颈动脉损伤后磷酸 Akt 水平的增加和新内膜形成的增强。 PTEN 缺陷的 SMC 在体外表现出基础条件下的自分泌生长表型，并表达与实验损伤后 SMC 中观察到的类似的细胞因子/趋化因子谱。初步数据表明，PTEN 缺失会激活转录因子 NF?B 和 HIF-1a；抑制 NFκB 或 HIF-1a 可阻断 PTEN 耗竭介导的特定趋化因子的上调。另一方面，我们的初步数据表明，SMC 中核受体 PPAR? 的激活会上调 PTEN，因此我们的研究将检验 PPAR? 的能力。激活抑制 SMC 增殖并通过上调 SMC PTEN 调节抗炎反应。总体而言，我们的初步数据提供证据表明，SMC PTEN 信号传导的改变是通过产生一系列趋化剂来驱动病理性血管重塑的关键启动决定因素，这些趋化剂通过旁分泌机制招募炎症/祖细胞并促进自分泌 SMC 增生反应。因此，SMC PTEN 信号传导的恢复有望逆转血管损伤引起的级联事件。我们将确定PTEN缺失对培养的PTEN缺失SMC中祖细胞/炎症细胞介质的SMC产生的影响和作用机制，并评估小鼠中SMC特异性缺失PTEN对趋化因子诱导的SMC增生以及目标一实验性血管损伤后新内膜形成过程中祖细胞和炎症细胞募集的相对贡献。在目标二中，我们将确定PPAR的作用？激动剂对 PTEN 上调和 SMC 生物学功能的影响，并确定 PTEN 调节在介导 PPAR 保护作用中的作用？激动剂对抗损伤诱导的血管重塑的发展。 公共卫生相关性：心脏病并发症仍然是西方社会死亡的主要原因。虽然血管成形术/支架部署和移植物已广泛用于治疗动脉粥样硬化，但这些手术中有很大一部分由于术后再狭窄而失败，其特征是显着的细胞生长和导致血管阻塞的炎症反应。因此，人们付出了大量的努力来确定调节这些过程的潜在机制，以减少干预后的血管闭塞。我们的研究旨在测试血管细胞表达的蛋白质 PTEN 在主动阻断趋化因子家族的表达方面的作用和作用机制，否则这些趋化因子会促进血管细胞生长和血管干预后的炎症反应。