Ecosanoids-Induced Vascular Growth During Injury

损伤期间 Ecosanoids 诱导血管生长

• 批准号: 7008601
• 负责人: KAFAIT U MALIK
• 金额: $ 35.64万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008601
• 关键词: JUN kinase; angiogenesis; angiotensin II; arachidonate; artery stenosis; cardiovascular injury; cell growth regulation; cytochrome P450; eicosanoid metabolism; eicosanoids; epidermal growth factor; growth factor receptors; hypertrophy; kinase inhibitor; laboratory rat; lipoxygenase; mitogen activated protein kinase; myogenesis; phospholipase A2; protein kinase C; protein tyrosine kinase; regeneration; vascular endothelium; vascular smooth muscle

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.

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.但是，这些AA代谢产物在损伤过程中促进血管重塑的机制尚不清楚。我们的初步观察是，a）脾酪氨酸激酶（p72syk）是一种非受体酪氨酸激酶，也在大鼠VSMC中表达，并被AA及其代谢物5（s） - ，12（s） - ，12（s） - ，15（s） - ，15（s）和20-heTe和Ang II（Ang II（An）释放的AA; b）p38有丝分裂激活蛋白激酶（MAPK）和pKczeta的抑制剂最小化ANG II诱导的p72 SYK激活； c）AA和HETE，例如Ang II，促进气球受伤的大鼠颈动脉的新内膜形成； d）Ang I在受伤的动脉中诱导的新生虫形成被主要的负P72 SYK衰减，使我们提出了以下中心假设：AA及其代谢物，主要是Hetes，通过激活P38 Mapk和PKCCzeta通过Epkczeta的激活来激活P72 SYK，通过激活P72 SYK通过Epcczeta通过Epyermal促进p72 Syk。为了检验该假设，将考虑以下特定目的：目标1。确定AA及其代谢物和ANG II在VSMC中的表达和激活。目的2。检查AA及其代谢物与ERK1/2，P38MAPK，JNK，PKCZETA，EGFR和P72 SYK之间的关系。目的。 3。研究P72 SYK对AA及其代谢产物（HETES）和ANG II的新内膜形成的贡献。目标4。确定P72 SYK在体外对VSMC迁移，增殖，肥大和细胞外基质产生的贡献，响应于AA，HETES和ANG II。拟议的研究应提高我们对损伤过程中血管重塑的机制的了解，并为开发用于治疗血管疾病的新型药物（包括再狭窄和动脉粥样硬化）提供了合理的方法。