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Current Pharmaceutical Biotechnology

Author(s): Xiaolei Cui, Yingping Tian, Yapei Zhao, Hengbo Gao, Dongqi Yao, Liang Liu and Yongjun Li*

DOI: 10.2174/1389201023666220324123224

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miR-199b-5p-AKAP1-DRP1 Pathway Plays a Key Role in ox-LDL-induced Mitochondrial Fission and Endothelial Apoptosis

Page: [1612 - 1622] Pages: 11

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Abstract

Background: Atherosclerosis (AS) remains prevalent despite hyperlipidemia-lowering therapies. Although multiple functions of miR-199b-5p have been implicated in cancers, its role in endothelial apoptosis and AS remains unclear. This study aimed to examine the role of miR-199b-5p in mitochondrial dynamics and endothelial apoptosis.

Methods: Human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL) were subjected to other treatments, followed by a series analysis. We found that ox-LDL-treated HUVECs were associated with miR-199b-5p downregulation, increased reactive oxygen species level, reduced adenosine triphosphate (ATP) production, mitochondrial fission, and apoptosis, whereas enhanced miR-199b-5p expression or applied mitochondrial division inhibitor 1 (Mdivi-1) markedly reversed these changes.

Results: Mechanistically, A-kinase anchoring protein 1 (AKAP1) was confirmed as a downstream target of miR-199b-5p by dual-luciferase activity reporter assay. AKAP1 overexpression reversed the anti-apoptotic effects of miR-199b-5p through the enhanced interaction of AKAP1 and dynamin protein 1 (DRP1) in ox-LDL–treated HUVECs. Moreover, miR-199b-5p downregulation, AKAP1 upregulation, and excessive mitochondrial fission were verified in human coronary AS endothelial tissues.

Conclusion: The miR-199b-5p-dependent regulation of AKAP1/DRP1 is required to inhibit hyperlipidemia- induced mitochondrial fission and endothelial injury and may be a promising therapeutic target for AS.

Keywords: miR-199b-5p, AKAP1, mitochondrial fission, DRP1, apoptosis, endothelial cell.

Graphical Abstract

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