Department of Gastroenterology, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Int Immunopharmacol. 2023 Jul;120:110280. doi: 10.1016/j.intimp.2023.110280. Epub 2023 May 20.
Hyperglycemia-induced chronic inflammation is a crucial risk factor that causes undesirable cardiac alternations in diabetic cardiomyopathy (DCM). Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that primarily regulates cell adhesion and migration. Based on recent studies, FAK is involved in inflammatory signaling pathway activation in cardiovascular diseases. Here, we evaluated the possibility of FAK as a therapeutic target for DCM.
A small molecular selective FAKinhibitor, PND-1186 (PND), was used to evaluate the effect of FAK on DCM in both high glucose-stimulated cardiomyocytes and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice.
Increased FAK phosphorylation was found in the hearts of STZ-induced T1DM mice. PND treatment significantly decreased the expression of inflammatory cytokines and fibrogenic markers in cardiac specimens of diabetic mice. Notably, these reductions were correlated with improved cardiac systolic function. Furthermore, PND suppressed transforming growth factor-β-activated kinase 1 (TAK1) phosphorylation and NF-κB activation in the hearts of diabetic mice. Cardiomyocytes were identified as the main contributor to FAK-mediated cardiac inflammation and the involvement of FAK in cultured primary mouse cardiomyocytes and H9c2 cells was identified. Both FAK inhibition or FAK deficiency prevented hyperglycemia-induced inflammatory and fibrotic responses in cardiomyocytes owing to the inhibition of NF-κB. Herein, FAK activation was revealed to FAK directly binding to TAK1, leading to activation of TAK1 and downstream NF-κB signaling pathway.
FAK is a key regulator of diabetes-associated myocardial inflammatory injury by directly targeting to TAK1.
高血糖诱导的慢性炎症是导致糖尿病心肌病（DCM）不良心脏改变的关键风险因素。黏着斑激酶（FAK）是一种非受体蛋白酪氨酸激酶，主要调节细胞黏附和迁移。基于最近的研究，FAK 参与了心血管疾病中炎症信号通路的激活。在这里，我们评估了 FAK 作为 DCM 治疗靶点的可能性。
使用小分子选择性 FAK 抑制剂 PND-1186（PND）来评估 FAK 在高糖刺激的心肌细胞和链脲佐菌素（STZ）诱导的 1 型糖尿病（T1DM）小鼠中对 DCM 的影响。
在 STZ 诱导的 T1DM 小鼠的心脏中发现 FAK 磷酸化增加。PND 治疗显著降低了糖尿病小鼠心脏标本中炎症细胞因子和纤维生成标志物的表达。值得注意的是，这些减少与心脏收缩功能的改善相关。此外，PND 抑制了糖尿病小鼠心脏中转化生长因子-β激活激酶 1（TAK1）的磷酸化和 NF-κB 的激活。心肌细胞被鉴定为 FAK 介导的心脏炎症的主要贡献者，并且鉴定了 FAK 在培养的原代小鼠心肌细胞和 H9c2 细胞中的参与。FAK 抑制或 FAK 缺乏均由于 NF-κB 的抑制而防止了高血糖诱导的心肌细胞中的炎症和纤维化反应。在此，FAK 的激活被揭示为 FAK 直接与 TAK1 结合，导致 TAK1 的激活和下游 NF-κB 信号通路。
FAK 通过直接靶向 TAK1 成为与糖尿病相关的心肌炎症损伤的关键调节因子。
