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，由于各种刺激的结合，例如 细胞因子和分布的血流。这些刺激导致促炎细胞粘附分子表达， 动脉粥样硬化中的早期事件，该事件将白细胞募集到活化的原始液中，导致慢性 炎症状态。尽管使用预防性药物用于这些常规风险，但 例如脂质降低和降压药是有益的，没有可用的治疗方法可用于 减少动脉粥样硬化的这些早期步骤。局灶性粘附激酶（FAK）是一种整合蛋白相关的蛋白 酪氨酸激酶在维持正常的血管生理学方面起着关键作用，而两者的变化变化 细胞因子和血流信号传导。我们的初步发现表明，内皮细胞的FAK抑制作用 （EC）预防肿瘤坏死因子-α（TNF-α）诱导的各种促炎分子的表达， 提出了FAK抑制作用的潜在“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）表达并降低巨噬细胞 招募，暗示FAK是动脉粥样硬化的潜在靶标。虽然NF-κB通常受到IκBα的抑制 炎症刺激导致IκBα迅速降解和NF-κB激活。然后由NF-κB更新IκBα 活性，从而抑制NF-κB。然而，在动脉粥样硬化中，由于持续而发生的NF-κB激活发生 随着IκBα的持续制造和降解，导致NF-κB活性的振荡刺激导致NF-κB活性。我们 发现EC中的FAK抑制作用阻止了由于IκBα稳定性提高而导致的NF-κB激活 在细胞质非活性中隔离NF-κB。此外，我们发现FAK的长期IκBα稳定 抑制作用可能是通过IκBα激酶（IKK）的FAK介导的酪氨酸磷酸化降低来介导的。拍摄 总之，我们的数据表明FAK活性通过 持续的NF-κB振荡。令人惊讶的是，FAK抑制剂阻滞了APOE的斑块形成 - / - 模型的模型 流动，表明FAK活性在流动信号传导中的潜在作用。综上所述，我们的中心假设是 FAK抑制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 通过该死的NF-κB振荡。在AIM-1中，我们将确定FAK作用的分子机制 在EC中，在TNF-α上保持持续的NF-κB信号传导。在AIM-2中，我们将评估 如果FAK介导的EC中的NF-κB活性通过使用药物和遗传FAK具有治疗潜力 动脉粥样硬化小鼠模型。这项研究将通过FAK介导的对动脉粥样硬化的新见解 EC中的NF-κB活性。此外，FAK抑制剂阻断持续NF-κB活性和斑块的能力 形成可能会在治疗血管炎症性疾病中提供新的治疗选择。