Focal adhesion kinase induces cardiac remodeling through NF-κB-mediated inflammatory responses in diabetic cardiomyopathy.

Bo Jin, Jiong Wang, Yi Chen, Wei Zuo, Bo Hong, Jie Li, Fang Huang, Mengpei Zhang, Yi Wang

International immunopharmacology 2023 Jul

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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. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Bo Jin, Jiong Wang, Yi Chen, Wei Zuo, Bo Hong, Jie Li, Fang Huang, Mengpei Zhang, Yi Wang. Focal adhesion kinase induces cardiac remodeling through NF-κB-mediated inflammatory responses in diabetic cardiomyopathy. International immunopharmacology. 2023 Jul;120:110280