Ecosanoids-Induced Vascular Growth During Injury

性状（由申请方提供）：通过脂氧合酶（LO）（主要是12（S）-羟基二十碳四烯酸（HETE）和细胞色素P450（CYP 450）（20-HETE））途径产生的AA代谢物，可引起血管收缩、血管平滑肌细胞（VSMC）增生和/或肥大。然而，这些AA代谢物在损伤过程中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（p72 Syk），一种非受体酪氨酸激酶，也在大鼠VSMC中表达，并且它被AA及其代谢产物5（S）-、12（S）-、15（S）-和20-HETE以及Ang II激活B）p38丝裂原活化蛋白激酶（MAPK）和PKCzeta的抑制剂使Ang II诱导的p72 Syk活化最小化; c）AA和HETE，如Ang II，促进球囊损伤的大鼠颈动脉中的新生内膜形成;和d）Ang I诱导的损伤动脉中的新生内膜形成被显性负性p72 Syk减弱，这使我们得出以下中心假设：AA及其代谢产物，主要是HETE，通过表皮生长因子受体（EGFR）激活p38 MAPK和PKCzeta，激活p72 Syk，促进新生内膜形成和狭窄。为了检验这一假设，将考虑以下具体目标：目标1。探讨AA及其代谢产物和Ang Ⅱ对VSMC中p72 Syk表达的影响。目标2.探讨AA及其代谢产物与VSMC中ERK 1/2、p38 MAPK、JNK、PKCzeta、EGFR和p72 Syk的关系。瞄准3.探讨p72 Syk在AA及其代谢产物（HETE）诱导的大鼠颈动脉内膜增生中的作用及血管紧张素II（Ang II）在球囊损伤后的作用。目标4。确定p72 Syk在体外对血管平滑肌细胞迁移、增殖、肥大和细胞外基质产生的作用，以响应AA、HETE和Ang II。这些研究将进一步加深我们对损伤后血管重塑机制的认识，并为开发治疗血管疾病（包括再狭窄和动脉粥样硬化）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.