{"title":"akap1稳定的TIMP-4通过失活NF-κB信号通路，减弱ang - ii诱导的血管平滑肌细胞氧化应激和炎症。","authors":"Yongxin Han, Xuejun Wu, Xin Shi, Guoliang Zhang, Xiaohan Wang, Chuanle Wang, Hua Zhou","doi":"10.1097/SHK.0000000000002557","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 (AUC).</p><p><strong>Conclusion: </strong>Our study provides evidence for the role of the AKAP1/TIMP-4/NF-κB pathway in Ang-II-induced VSMC inflammation and oxidative stress.</p>","PeriodicalId":21667,"journal":{"name":"SHOCK","volume":" ","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"AKAP1-stabilized TIMP-4 attenuates Ang-II-induced oxidative stress and inflammation in vascular smooth muscle cells by inactivating the NF-κB signaling.\",\"authors\":\"Yongxin Han, Xuejun Wu, Xin Shi, Guoliang Zhang, Xiaohan Wang, Chuanle Wang, Hua Zhou\",\"doi\":\"10.1097/SHK.0000000000002557\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 (AUC).</p><p><strong>Conclusion: </strong>Our study provides evidence for the role of the AKAP1/TIMP-4/NF-κB pathway in Ang-II-induced VSMC inflammation and oxidative stress.</p>\",\"PeriodicalId\":21667,\"journal\":{\"name\":\"SHOCK\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-02-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"SHOCK\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/SHK.0000000000002557\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CRITICAL CARE MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"SHOCK","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/SHK.0000000000002557","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
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 (AUC).
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.
期刊介绍：
SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.
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