AKAP1-STABILIZED TIMP-4 ATTENUATES ANG-II-INDUCED OXIDATIVE STRESS AND INFLAMMATION IN VASCULAR SMOOTH MUSCLE CELLS BY INACTIVATING THE NF-ΚB SIGNALING

Background: Oxidative stress and inflammation are key factors contributing to the complex pathogenesis of abdominal aortic aneurysm (AAA). Tissue inhibitor of metalloproteinases-4 (TIMP-4) expression is reduced in AAA patients. In this study, we investigated the impact of TIMP-4 on the phenotype alterations induced by angiotensin II (Ang-II) in human vascular smooth muscle cells (VSMCs). Methods: The expression profiling of TIMP-4 and A-kinase anchoring protein (AKAP1) in AAA samples was analyzed using the GSE7084 and GSE140947 datasets. Levels of TIMP-4 and AKAP1 in Ang-II-exposed VSMCs and AAA tissues and serum samples were detected. RNA immunoprecipitation (RIP) experiment and mRNA stability analysis were used to examine the interaction between AKAP1 and TIMP-4 mRNA. The impact of the AKAP1/TIMP-4 cascade on Ang-II-induced VSMC phenotype alterations was determined by evaluating cell viability, apoptosis, oxidative stress, and inflammation. Results: TIMP-4 and AKAP1 levels were decreased in Ang-II-exposed VSMCs. Increased TIMP-4 expression protected VSMCs against Ang-II-evoked growth impairment in vitro . Moreover, TIMP-4 upregulation diminished Ang-II-evoked oxidative stress and inflammation in VSMCs. Mechanistically, RNA binding protein (RBP) AKAP1 stabilized TIMP-4 mRNA to elevate TIMP-4 expression. TIMP-4 reduction partially abrogated AKAP1-driven suppression on oxidative stress, inflammation, matrix metalloproteinase (MMP9) expression, and nuclear factor kappa B (NF-κB) pathway activation in Ang-II-exposed VSMCs. Additionally, TIMP-4 and AKAP1 levels were downregulated in AAA patients in their AAA tissues and serum samples. TIMP-4 and AKAP1 had good diagnostic values for AAA with high area under the ROC curve. Conclusion: Our study provides evidence for the role of the AKAP1/TIMP-4/NF-κB pathway in Ang-II-induced VSMC inflammation and oxidative stress.