Regulation of smooth muscle cell function by CD44 in cardiovascular disease

CD44在心血管疾病中调节平滑肌细胞功能

• 批准号: 7653544
• 负责人: Ellen Pure'
• 金额: $ 42.71万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653544
• 关键词: Abbreviations; Accounting; Activation Analysis; Acute; Affect; Angioplasty; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Binding; Biological; Blood Vessels; Bone Marrow; C57BL/6 Mouse; CCND1 gene; CD44 Antigens; CD44 gene; Cardiovascular Diseases; Cause of Death; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell physiology; Cells; Chimera organism; Coronary; Cyclin D1; Cyclin-Dependent Kinases; Development; Endothelial Cells; Environment; Equilibrium; Event; Extracellular Matrix; Gene Expression; Genetic; Glycosaminoglycans; Hyaluronan; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knock-out; Knockout Mice; Ligands; Mediating; Mitogens; Molecular Weight; Monitor; Mus; Myocardial Infarction; Non-Steroidal Anti-Inflammatory Agents; Patients; Pharmaceutical Preparations; Phase; Play; Prevention; Procedures; Public Health; Regulation; Risk; Role; Rupture; Signal Transduction; Site; Smooth Muscle Myocytes; Stents; Testing; Therapeutic Intervention; Time; Tissues; United States; atherogenesis; bcl-1 Genes; cell growth; cell type; implantation; in vivo; injured; minimally invasive; neointima formation; novel; prevent; public health relevance; research study; response; response to injury; restenosis; selective expression; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Proliferation of vascular smooth muscle cells (VSMCs) is fundamental to neointima formation, a hallmark of cardiovascular disease (CVD). The extracellular matrix (ECM) plays an important role in regulating VSMCs, and we have studied the effects of the ECM component hyaluronan (HA) and the HA receptor, CD44, on VSMC proliferation and neointima formation. We show that HA and CD44 have bifunctional effects on VSMC proliferation and activation. In vitro, the native high molecular weight form of HA (HMW-HA) antagonizes mitogen-induced S phase entry of VSMCs while the lower molecular weight forms of HA (LMW- HA) that accumulate at sites of inflammation synergize with mitogens to stimulate VSMC S phase entry. Both effects are mediated by CD44, and result from differential regulation of Rac- and ERK-dependent signaling to cyclin D1. HMW-HA binding to CD44 inhibits GTP-loading of Rac and Rac-dependent signaling to the cyclin D1 gene while LMW-HA binding to CD44 stimulates ERK-dependent cyclin D1 gene expression. A similar bifunctionality can be detected in vivo as genetic deletion of CD44 enhances the response to injury in C57BL/6 mice but inhibits atherogenesis in apoE-deficient mice. Since the ratio of LMW-HA to HMW-HA is directly related to the extent of inflammation, and the inflammatory environment is much greater in apoE-deficient mice as compared to B6 mice, we hypothesize that the biological response to CD44 in vivo is directed by the degree of local inflammation, and that changes in the inflammatory milieu can reconcile the seemingly contradictory effects of CD44 on VSMC activation and neointima formation during the response to vascular injury and atherogenesis. In Aim 1, we will compare the effects of CD44 on VSMC proliferation and neointima formation in vascular injury as we modulate inflammation, and we will exploit our recently developed floxed CD44 mouse to distinguish the effects of CD44 on SMCs and inflammatory cells. In Aim 2, we will perform similar experiments monitoring the effect of inflammation and cell type-specific CD44 expression on neointima formation during atherogenesis. In Aim 3, we will attempt to eliminate the bifunctional response of CD44 on VSMC activation by performing fine-wire injury on mice carrying an SMC-specific deletion of Rac1. PUBLIC HEALTH RELEVANCE: Cardiovascular disease due to atherosclerosis, the number one cause of death in the United States, is characterized by neointima formation due to inflammation and vascular smooth muscle cell proliferation. The balance between inflammation and formation of smooth muscle cell-rich fibrotic caps in part determines the risk to rupture of atherosclerotic plaques and acute events such as heart attacks. Minimally invasive percutaneous revascularization procedures such as angioplasty and stent implantation are currently considered the treatment of choice for the prevention and treatment of acute coronary events in many patients. However, such interventions are associated with a significant risk of vascular restenosis due to excessive vascular smooth cell proliferation in response to injury caused by the intervention. Modulating smooth muscle cell proliferation may be an important approach to minimize the risk of acute events in patients with atherosclerosis, and may also prevent restenosis following physical interventions, thereby greatly reducing the risks associated with standard therapeutic interventions. The proposed studies will define mechanisms that regulate smooth muscle cell growth and thus provide novel targets for treatment of atherosclerosis and restenosis.

描述（由申请人提供）：血管平滑肌细胞（VSMCs）的增殖是新生内膜形成的基础，是心血管疾病（CVD）的标志。细胞外基质（extracellular matrix， ECM）在VSMC的调控中起着重要作用，我们研究了ECM成分透明质酸（hyaluronan， HA）和HA受体CD44对VSMC增殖和新生内膜形成的影响。我们发现HA和CD44对VSMC的增殖和激活具有双重作用。在体外实验中，天然的高分子量HA （HMW-HA）可拮抗有丝分裂原诱导的VSMC进入S期，而积聚在炎症部位的低分子量HA （LMW- HA）可与有丝分裂原协同作用，刺激VSMC进入S期。这两种作用都是由CD44介导的，并且是由Rac-和erk依赖性信号传导到cyclin D1的差异调控引起的。HMW-HA结合CD44抑制Rac的gtp负载和Rac依赖的cyclin D1基因信号传导，而LMW-HA结合CD44刺激erk依赖的cyclin D1基因表达。在体内可以检测到类似的双功能，CD44基因缺失增强了C57BL/6小鼠对损伤的反应，但抑制了apoe缺陷小鼠的动脉粥样硬化。由于LMW-HA与HMW-HA的比例与炎症程度直接相关，并且apoe缺陷小鼠的炎症环境比B6小鼠大得多，我们假设体内对CD44的生物学反应是由局部炎症程度指导的，炎症环境的变化可以调和CD44在血管损伤和动脉粥样硬化反应中对VSMC激活和新内膜形成的看似矛盾的作用。在Aim 1中，我们将比较CD44在调节炎症时对血管损伤中VSMC增殖和新内膜形成的影响，我们将利用我们最近开发的floxed CD44小鼠来区分CD44对SMCs和炎症细胞的影响。在Aim 2中，我们将进行类似的实验，监测炎症和细胞类型特异性CD44表达对动脉粥样硬化过程中新内膜形成的影响。在Aim 3中，我们将尝试通过对携带smc特异性缺失的Rac1的小鼠进行细丝损伤来消除CD44对VSMC激活的双功能反应。公共卫生相关性：动脉粥样硬化引起的心血管疾病是美国的头号死亡原因，其特点是炎症和血管平滑肌细胞增殖引起的新内膜形成。炎症和富含平滑肌细胞的纤维化帽形成之间的平衡在一定程度上决定了动脉粥样硬化斑块破裂和心脏病发作等急性事件的风险。微创经皮血管重建术，如血管成形术和支架植入术，目前被认为是许多患者预防和治疗急性冠状动脉事件的首选治疗方法。然而，这种干预与血管再狭窄的显著风险相关，因为干预引起的损伤会导致血管平滑细胞过度增殖。调节平滑肌细胞增殖可能是降低动脉粥样硬化患者急性事件风险的重要途径，也可能预防物理干预后的再狭窄，从而大大降低与标准治疗干预相关的风险。这些研究将明确调节平滑肌细胞生长的机制，从而为动脉粥样硬化和再狭窄的治疗提供新的靶点。