Role of Nogo-B in Mediating the Vascular Effects of Alcohol

Nogo-B 在介导酒精血管效应中的作用

• 批准号: 8538869
• 负责人: EILEEN M. REDMOND
• 金额: $ 20.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538869
• 关键词: Adult; Alcohol consumption; Alcohols; Apoptosis; Atherosclerosis; Attenuated; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Differentiation process; Cell Growth Processes; Cell Proliferation; Cells; Clinical; Complication; Coronary artery; Data; Development; Endothelial Cells; Ethanol; Functional disorder; Gel; Gene Targeting; Growth; Human; In Vitro; Injury; Integral Membrane Protein; Ischemic Stroke; Knock-out; Lesion; Ligation; Lipoproteins; Mediating; Membrane Microdomains; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Pathogenesis; Pathway interactions; Peripheral Vascular Diseases; Phenotype; Plasma; Play; Pluronics; Process; Regulation; Reporting; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Testing; Time; Vascular Diseases; Vascular remodeling; alcohol effect; atherogenesis; attenuation; cardiovascular disorder therapy; cell growth; cell type; design; expression vector; feeding; human RTN4 protein; in vivo; innovation; interest; intima media; intimal medial thickening; loss of function; migration; mortality; mouse model; notch protein; novel; protective effect; receptor; receptor expression; research study; response; response to injury

DESCRIPTION (provided by applicant): Moderate consumption of alcohol (ethanol) is a negative risk factor for atherosclerosis and its clinical sequelae myocardial infarction, ischemic stroke and peripheral vascular disease. Little is known about the precise cell signaling and molecular mechanisms whereby ethanol may elicit its putative cardioprotective effects. We have previously reported that while EtOH stimulates the growth and migration of endothelial cels (EC), it inhibits vascular smooth muscle cell (SMC) growth and migration. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, the opposing effects of EtOH on these vascular cells might be expected to be synergistically cardioprotective and thus are of considerable clinical interest. Moreover, our preliminary data show that daily moderate alcohol feeding markedly inhibits intima-media thickening following carotid ligation injury in the mouse. EC and SMC express Notch receptors and several groups, including ours, have described a critical role for Notch signaling in the regulation of adult EC and SMC differentiation, proliferation and apoptosis. The expression of several components of the Notch pathway, including receptors and downstream target genes hes and hrt, are altered after experimentally induced vascular injury. Our data also demonstrate a differential effect of EtOH on Notch signaling in EC and SMC, - stimulatory and inhibitory, respectively, and further, implicate this pathway in mediating both EtOH's promotion of EC proliferation and it's attenuation of SMC proliferation. The transmembrane protein Nogo-B, expressed by both EC and SMC and in intact vessels, has recently been identified as a regulator of vascular remodeling, limiting the progression of vascular lesions after injury. Of interest, Nogo-B reportedly has opposing effects on vascular cells, promoting the migration of EC, but inhibiting the migration of SMC, possibly reflecting differences in receptor expression between the two cell types. Our preliminary data show that EtOH modulates Nogo-B expression in vascular cells. Despite a role for both Notch and Nogo in vascular remodeling regulation, and a differential effect of each in EC and SMC with respect to phenotype regulation, no studies to date have investigated an interaction of Nogo and Notch, much less as targets for alcohol. Our central hypothesis is that ethanol stimulates EC, and inhibits SMC growth and thus inhibits vascular remodeling in a Notch-dependent manner, mediated via Nogo-B. We will test this hypothesis using cultured human coronary artery EC and SMC in vitro in conjunction with in vivo studies utilizing the carotid ligation 'flow-restriction' model of vascular injury and remodeling in the mouse. Since changes in EC and SMC growth plays a prominent role in the pathogenesis of vascular disease, modulation of these processes by ethanol in a Nogo-B-dependent fashion represents a novel and potentially important mechanism underlying ethanol's cardioprotective effect. Because the mortality from cardiovascular disease is so high, deciphering a mechanism whereby a substance can protect against it is clearly of major clinical importance and significance. !

描述（由申请人提供）：适度饮酒是动脉粥样硬化及其临床后遗症心肌梗死、缺血性中风和周围血管疾病的负性危险因素。乙醇可能引发其假定的心脏保护作用的确切细胞信号传导和分子机制尚不清楚。我们之前报道过，虽然EtOH刺激内皮细胞（EC）的生长和迁移，但它抑制血管平滑肌细胞（SMC）的生长和迁移。鉴于EC和SMC在动脉粥样硬化病理生理中的关键作用，EtOH对这些血管细胞的相反作用可能具有协同心脏保护作用，因此具有相当大的临床意义。此外，我们的初步数据显示，每日适量饮酒可显著抑制小鼠颈动脉结扎损伤后的内膜-中膜增厚。EC和SMC表达Notch受体，包括我们在内的几个研究小组已经描述了Notch信号在成人EC和SMC分化、增殖和凋亡调控中的关键作用。Notch通路的几个组成部分，包括受体和下游靶基因hes和hrt的表达在实验诱导的血管损伤后发生改变。我们的数据还显示了EtOH对EC和SMC Notch信号通路的不同作用，分别为-刺激和抑制，并进一步暗示该通路介导了EtOH促进EC增殖和抑制SMC增殖的作用。跨膜蛋白Nogo-B，由EC和SMC在完整血管中表达，最近被确定为血管重塑的调节剂，限制损伤后血管病变的进展。有趣的是，据报道Nogo-B对血管细胞有相反的作用，促进EC的迁移，但抑制SMC的迁移，这可能反映了两种细胞类型之间受体表达的差异。我们的初步数据表明，EtOH可以调节血管细胞中Nogo-B的表达。尽管Notch和Nogo在血管重塑调节中都有作用，而且它们在EC和SMC的表型调节中都有不同的作用，但迄今为止还没有研究调查Nogo和Notch的相互作用，更不用说作为酒精的靶点了。我们的中心假设是乙醇刺激EC，抑制SMC生长，从而通过Nogo-B介导以缺口依赖的方式抑制血管重塑。我们将使用体外培养的人类冠状动脉EC和SMC来验证这一假设，并结合使用小鼠颈动脉结扎“血流限制”血管损伤和重塑模型进行体内研究。由于EC和SMC生长的变化在血管疾病的发病机制中起着重要作用，乙醇以nogo - b依赖的方式调节这些过程代表了乙醇具有心脏保护作用的一种新的、潜在的重要机制。由于心血管疾病的死亡率如此之高，破译一种物质可以预防心血管疾病的机制显然具有重大的临床重要性和意义。！

项目成果

Embryonic rat vascular smooth muscle cells revisited - a model for neonatal, neointimal SMC or differentiated vascular stem cells?

• DOI: 10.1186/2045-824x-6-6
• 发表时间: 2014-03-15
• 期刊: Vascular cell
• 作者: Kennedy E;Hakimjavadi R;Greene C;Mooney CJ;Fitzpatrick E;Collins LE;Loscher CE;Guha S;Morrow D;Redmond EM;Cahill PA
• 通讯作者: Cahill PA

Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

• DOI: 10.1371/journal.pone.0084122
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Redmond EM;Liu W;Hamm K;Hatch E;Cahill PA;Morrow D
• 通讯作者: Morrow D

Adult vascular smooth muscle cells in culture express neural stem cell markers typical of resident multipotent vascular stem cells.

• DOI: 10.1007/s00441-014-1937-2
• 发表时间: 2014-10
• 期刊: Cell and tissue research
• 影响因子: 3.6
• 作者: Kennedy E;Mooney CJ;Hakimjavadi R;Fitzpatrick E;Guha S;Collins LE;Loscher CE;Morrow D;Redmond EM;Cahill PA
• 通讯作者: Cahill PA