Ecosanoids-Induced Vascular Growth During Injury

描述（由申请人提供）：通过脂氧合酶（LO）衍生的AA代谢物主要是12(S)-羟基二碳四烯酸（HETE）和细胞色素P450 (CYP450) (20-HETE)，途径，引起血管收缩，血管平滑肌细胞（VSMC）增生和/或肥大。然而，这些AA代谢物在损伤期间促进血管重塑的机制尚不清楚。我们初步观察到a)脾酪氨酸激酶（p72Syk）是一种非受体酪氨酸激酶，在大鼠VSMC中也有表达，它被AA及其代谢物5(S)-、12(S)-、15(S)和20-HETE以及引起AA释放的Ang II激活；b) p38丝裂原活化蛋白激酶（MAPK）和PKCzeta抑制剂可减少Ang ii诱导的p72 Syk活化；c) AA和HETEs与Ang II一样，促进球囊损伤大鼠颈动脉新生内膜的形成；d)损伤动脉中Ang I诱导的新内膜形成被p72 Syk显性阴性减弱，这使我们得出以下中心假设：AA及其代谢物，主要是HETEs，通过表皮生长因子受体（EGFR）激活p38 MAPK和PKCzeta，从而激活p72 Syk，从而促进新内膜形成和狭窄。为了验证这一假设，将考虑以下具体目标：目标1。目的：探讨AA及其代谢物和angii在VSMC中的表达及活化作用。目标2。探讨AA及其代谢物与VSMC中ERK1/2、p38MAPK、JNK、PKCzeta、EGFR和p72 Syk的关系。目标。3。目的探讨p72 Syk在大鼠颈动脉球囊损伤中对AA及其代谢物（HETEs）和Ang II在体内形成新内膜的作用。目标4。确定p72 Syk在体外响应AA、HETEs和Ang II时对vsmc迁移、增殖、肥大和细胞外基质生成的贡献。这些研究将有助于我们进一步了解损伤过程中血管重构的机制，并为开发治疗血管再狭窄和动脉粥样硬化等血管疾病的新药物提供合理的途径。

DESCRIPTION (provided by applicant): AA metabolites derived via lipoxygenase (LO) mainly 12(S)-hydroxyeicosatetraenoic acid (HETE) and cytochrome P450 (CYP450) (20-HETE), pathways, cause vasoconstriction, vascular smooth muscle cell (VSMC) hyperplasia and/or hypertrophy. However, the mechanism by which these AA metabolites promote vascular remodeling during injury is not well understood. Our preliminary observations that a) spleen tyrosine kinase (p72Syk), a non-receptor tyrosine kinase, is also expressed in rat VSMC and it is activated by AA and its metabolites 5(S)-, 12(S)-, 15(S) and 20-HETE and also Ang II (which causes release of AA); b) inhibitors of p38 mitogen activated protein kinase (MAPK) and PKCzeta minimize Ang II-induced p72 Syk activation; c) AA and HETEs, like Ang II, promote neointima formation in balloon injured rat carotid artery; and d) Ang I induced neointima formation in the injured artery is attenuated by dominant negative p72 Syk have led us to the following central hypothesis: AA and its metabolites, mainly HETEs, promote neointima formation and stenosis by activating p72 Syk via activation of p38 MAPK and PKCzeta through the epidermal growth factor receptor (EGFR). To test this hypothesis, the following specific aims will be considered: Aim 1. To determine the expression and activation of p72 Syk by AA and its metabolite and Ang II in VSMC. Aim 2. To examine the relationship between AA and its metabolites and ERK1/2, p38MAPK, JNK, PKCzeta, EGFR and p72 Syk in VSMC. Aim. 3. To investigate the contribution of p72 Syk to neointima formation by AA and its metabolites (HETEs) and of Ang II to in vivo in balloon injured rat carotid artery. Aim 4. To determine the contribution of p72 Syk in vitro to VSMC-migration, proliferation, hypertrophy and extracellular matrix production in response to AA, HETEs, and Ang II. The proposed studies should advance our knowledge of the mechanism involved in vascular remodeling during injury and provide a rational approach for the development of novel agents for the treatment vascular diseases including restenosis and atherosclerosis.