2. Academic Validation
  3. Reduction in MicroRNA-4488 Expression Induces NFκB Translocation in Venous Endothelial Cells Under Arterial Flow

Reduction in MicroRNA-4488 Expression Induces NFκB Translocation in Venous Endothelial Cells Under Arterial Flow

  • Cardiovasc Drugs Ther. 2021 Feb;35(1):61-71. doi: 10.1007/s10557-020-06944-8.
Shao-Yu Fang 1 2,  Chia-Wei Huang 1 2 3,  Tzu-Chieh Huang 1 2 3,  Anjali Yadav 1 2 4,  Jeng-Jiann Chiu 5,  Chia-Ching Wu 6 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 2 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 3 International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan.
  • 4 Taiwan International Graduate Program in Interdisciplinary Neuroscience, Academia Sinica, Taipei, Taiwan.
  • 5 Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County, Taiwan.
  • 6 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan. joshccwu@mail.ncku.edu.tw.
  • 7 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. joshccwu@mail.ncku.edu.tw.
  • 8 International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan. joshccwu@mail.ncku.edu.tw.
  • 9 Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan. joshccwu@mail.ncku.edu.tw.
  • 10 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 701, Taiwan. joshccwu@mail.ncku.edu.tw.
PMID: 32902737 DOI: 10.1007/s10557-020-06944-8
Abstract

Purpose: Little is known about the molecular interactions among inflammatory responses that damage venous endothelial cells (vECs) during venous-to-arterial flow transition in vein graft diseases. Because arterial flow triggers excessive Autophagy and inflammation in vECs, this study aimed to investigate the mediator of inflammation and methods to prevent vEC damage.

Methods: Arterial laminar shear stress (ALSS; 12 dynes/cm2) was applied to vECs via in vitro and ex vivo perfusion systems. Inflammation in vECs was measured using inflammatory protein markers, NFκB translocation, cyclooxygenase-2 (COX-2) and COX-2 and NFκB promoter assays. The involvement of microRNA-4488 (miR-4488) was measured and confirmed by altering the specific miR using a miR-4488 mimic or inhibitor. The potential anti-inflammatory drugs and/or nitric oxide (NO) donor L-arginine (L-Arg) to prevent damage to vECs under ALSS was investigated.

Results: ALSS triggered Reactive Oxygen Species production, excessive Autophagy, COX-2 protein expression, and NFκB translocation during vEC inflammation. Reduction in miR-4488 expression was detected in inflamed vECs treated with LPS, lipopolysaccharide (LPS) TNFα, and ALSS. Transfection of miR-4488 mimic (50 nM) prior to ALSS application inhibited the accumulation of inflammatory proteins as well as the translocation of NFκB. Combined treatment of vECs with COX-2-specific inhibitor (SC-236) and L-Arg alleviated the ALSS-induced inflammatory responses. Protective effects of the combined treatment on vECs against ALSS-induced damage were abolished by the application of miR-4488 inhibitor.

Conclusion: We showed that ALSS triggered the COX-2/NFκB pathway to induce vEC inflammation with a reduction in miR-4488. Combination of SC-236 and L-Arg prevented ALSS-induced vEC damage, thus, shows high potential for preventing vein graft diseases.

Keywords

Arterial shear stress; COX-2; NFκB; Venous endothelial cells; miR-4488.

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