Role of FAK in vascular inflammation

FAK 在血管炎症中的作用

• 批准号: 9886279
• 负责人: Steve Lim
• 金额: $ 42.65万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886279
• 关键词: Antihypertensive Agents; Ants; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Blood; Blood Vessels; Blood flow; CD47 gene; Cardiovascular Diseases; Cause of Death; Cell Adhesion Molecules; Cholesterol; Chronic; Cytoplasm; Data; Defect; Disease; Endothelial Cells; Endothelium; Event; Focal Adhesion Kinase 1; Gene Expression; Genetic; I Kappa B-Alpha; IKK alpha; Inflammation; Inflammatory; Lead; Leukocytes; Lipids; Mediating; Modeling; Molecular; Mus; NF-kappa B; Nuclear; Pharmacology; Phosphotransferases; Physiology; Play; Prevention strategy; Protein Tyrosine Kinase; Recovery; Risk; Role; Signal Transduction; Stimulus; Stroke; TNF gene; Testing; Therapeutic; Tyrosine Phosphorylation; Vascular Cell Adhesion Molecule-1; atherogenesis; chronic inflammatory disease; cytokine; in vivo; insight; kinase inhibitor; macrophage; mouse model; novel therapeutics; prevent; recruit; response; vascular inflammation

Atherosclerosis is a chronic inflammatory disease that arises due to a combination of various stimuli, such as cytokines and disturbed blood flow. These stimuli result in pro-inflammatory cell adhesion molecule expression, an early event in atherogenesis, which recruit leukocytes to the activated endothelium, leading to a chronic inflammatory state. Although the use of preventative pharmacological approaches for these conventional risks, such as lipid lowering and antihypertensive drugs, have been beneficial, there is no treatment available to reduce these early steps of atherogenesis. Focal adhesion kinase (FAK) is an integrin-associated protein tyrosine kinase that plays a critical role in maintaining normal vascular physiology upon changes in both cytokine and blood flow signaling. Our preliminary findings have revealed that FAK inhibition in endothelial cells (EC) prevented tumor necrosis factor-α (TNF-α)-induced expression of various pro-inflammatory molecules, suggesting a potential “ant-inflammatory role” for FAK inhibition. Interestingly, in ApoE-/- model, FAK inhibitor was able to block vascular cell adhesion molecule-1 (VCAM-1) expression and reduced macrophage recruitment, implicating FAK as a potential target for atherosclerosis. While NF-κB is normally inhibited by IκBα, inflammatory stimuli lead to rapid IκBα degradation and NF-κB activation. IκBα is then upregulated by NF-κB activity, thus inhibiting NF-κB. In atherosclerosis, however, sustained NF-κB activation occurs due to continued inflammatory stimuli, which leads to oscillations of NF-κB activity as IκBα is continually made and degraded. We discovered that FAK inhibition in ECs prevented sustained NF-κB activation due to increased stability of IκBα, sequestering NF-κB in cytoplasm inactive. Further, we found that this long term IκBα stabilization by FAK inhibition may be mediated by reduced FAK-mediated tyrosine phosphorylation of IκBα kinase (IKK). Taken together, our data suggest that FAK activity drives TNF-α-induced pro-inflammatory gene expression through sustained NF-κB oscillations. Surprisingly, FAK inhibitor blocks plaque formation in ApoE -/- model of disturbed flow, indicating a potential role of FAK activity in flow signaling. Taken together, our central hypothesis is that FAK inhibition may prevent atherosclerosis by blocking stimuli-induced pro-inflammatory molecule expression via dampened NF-κB oscillations. In aim-1, we will determine the molecular mechanism of FAK action in maintaining sustained NF-κB signaling upon TNF-α and disturbed blood flow in ECs. In aim-2, we will evaluate if FAK-mediated NF-κB activity in ECs has therapeutic potential by using pharmacological and genetic FAK atherosclerosis mouse models. This study will produce new insights into atherogenesis via FAK-mediated NF-κB activity in ECs. Furthermore, FAK inhibitor's ability to block sustained NF-κB activity and plaque formation might provide a new therapeutic option in the treatment vascular inflammatory diseases.

动脉粥样硬化是一种慢性炎症性疾病，其起因于多种刺激的组合，例如 细胞因子和血流紊乱。这些刺激导致促炎细胞粘附分子表达， 这是动脉粥样硬化形成的早期事件，它将白细胞募集到活化的内皮细胞，导致慢性炎症。 炎症状态尽管使用预防性药理学方法来预防这些传统风险， 例如降脂和抗高血压药物，已经是有益的，但是没有可用的治疗， 减少动脉粥样硬化形成的早期步骤。粘着斑激酶（FAK）是一种整合素相关蛋白 酪氨酸激酶，在维持正常血管生理学中起关键作用， 细胞因子和血流信号传导。我们的初步研究结果表明，抑制内皮细胞中的FAK (EC)阻止肿瘤坏死因子-α（TNF-α）诱导的各种促炎分子的表达， 提示FAK抑制的潜在“抗炎作用”。有趣的是，在ApoE-/-模型中，FAK抑制剂 能够阻断血管细胞粘附分子-1（VCAM-1）的表达， 招募，暗示FAK是动脉粥样硬化的潜在靶点。虽然NF-κB通常被IκBα抑制， 炎症刺激导致IκBα快速降解和NF-κB激活。IκBα随后被NF-κB上调 活性，从而抑制NF-κB。然而，在动脉粥样硬化中，持续的NF-κB活化是由于持续的 炎症刺激，导致NF-κB活性的振荡，因为IκBα不断产生和降解。我们 发现由于IκBα的稳定性增加，抑制EC中的FAK阻止了持续的NF-κB活化， 将NF-κB隔离在细胞质中失活。此外，我们还发现FAK对IκBα的长期稳定作用 抑制作用可能是通过降低IκBα激酶（IKK）的FAK介导的酪氨酸磷酸化来介导的。采取 总之，我们的数据表明，FAK活性驱动TNF-α诱导的促炎基因表达， 持续的NF-κB振荡。令人惊讶的是，FAK抑制剂阻断了ApoE -/-模型中的斑块形成， 流动，表明FAK活性在流动信号传导中的潜在作用。综上所述，我们的核心假设是， 抑制FAK可能通过阻断刺激诱导的促炎分子表达来预防动脉粥样硬化 通过抑制NF-κB振荡。在aim-1中，我们将确定FAK作用的分子机制， 维持TNF-α作用下NF-κB信号的持续性，干扰内皮细胞的血流。在aim-2中，我们将评估 如果FAK介导的NF-κB活性在EC中具有通过使用药理学和遗传学FAK的治疗潜力 动脉粥样硬化小鼠模型。这项研究将对FAK介导的动脉粥样硬化形成产生新的见解。 内皮细胞NF-κB活性。此外，FAK抑制剂阻断持续的NF-κB活性和斑块的能力， 为治疗血管炎性疾病提供了一种新的治疗选择。