Focal adhesion kinase induces cardiac remodeling through NF-κB-mediated inflammatory responses in diabetic cardiomyopathy
Focal adhesion kinase induces cardiac remodeling through NF-κB-mediated inflammatory responses in diabetic cardiomyopathy
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DOI：
10.1016/j.intimp.2023.110280
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发表时间：
2023-05-20
影响因子：
5.6
通讯作者：
Wang，Yi
中科院分区：
文献类型：
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作者：
Jin，Bo;Wang，Jiong;Wang，Yi
背景高血糖引起的慢性炎症是糖尿病心肌病（DCM）心脏异常的重要危险因素。粘着斑激酶（FAK）是一种非受体蛋白酪氨酸激酶，主要调节细胞粘附和迁移。近年来的研究表明，FAK参与了心血管疾病炎症信号通路的激活。在这里，我们评估的可能性FAK作为一个治疗靶点为DCM.MethodsA小分子选择性FAK抑制剂，PND-1186（PND），被用来评估FAK对DCM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.ResultsFAK磷酸化增加被发现在STZ诱导的T1 DM小鼠的心脏。PND治疗显著降低糖尿病小鼠心脏标本中炎性细胞因子和纤维化标记物的表达。值得注意的是，这些降低与心脏收缩功能改善相关。此外，PND还能抑制糖尿病小鼠心脏中转化生长因子-β-激活激酶1（TAK 1）的磷酸化和NF-κB的活化。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H9 c2细胞中的参与。FAK抑制或FAK缺乏均能通过抑制NF-κB而防止高血糖诱导的心肌细胞炎症和纤维化反应。结论FAK通过直接作用于TAK 1，激活TAK 1及其下游的NF-κB信号通路，是糖尿病心肌炎性损伤的重要调控因子。
BackgroundHyperglycemia-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.MethodsA small molecular selective FAK inhibitor, 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.ResultsIncreased 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.ConclusionsFAK is a key regulator of diabetes-associated myocardial inflammatory injury by directly targeting to TAK1.