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Research Paper|Volume 12, Issue 8|pp 7511—7533

Expression of Nik-related kinase in smooth muscle cells attenuates vascular inflammation and intimal hyperplasia

Yi-Jhu Lu1, Yee-Jee Jan2, Bor-Sheng Ko3,4, Shu-Man Liang1, Lujen Chen2, Chih-Cheng Wu1,5,6, Chih-Hui Chin7, Cheng-Chin Kuo1, Shaw-Fang Yet1, Jun-Yang Liou1,8
  • 1Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan
  • 2Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan
  • 3Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
  • 4Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei 100, Taiwan
  • 5Cardiovascular Center, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu City 300, Taiwan
  • 6Department of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
  • 7Cardiovascular Center, Cathay General Hospital, Taipei 106, Taiwan
  • 8Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
* Equal contribution
Received: October 22, 2019Accepted: March 2, 2020Published: April 24, 2020
https://doi.org/10.18632/aging.103104

Copyright © 2020 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Inflammation of the vascular microenvironment modulates distinct types of vascular cells, and plays important roles in promoting atherosclerosis, stenosis/restenosis, and vascular-related diseases. Nik-related kinase (Nrk), a member of the Ste20-type kinase family, has been reported to be selectively expressed in embryonic skeletal muscle. However, whether Nrk is expressed in adult vascular smooth muscle, and if it influences intimal hyperplasia is unclear. Here, we found that Nrk is abundantly expressed in cultured vascular smooth muscle cells (VSMC) and mouse arterial intima. Treatment of mouse VSMCs with lipopolysaccharide (LPS) or platelet-derived growth factor significantly reduced Nrk expression. In addition, expression of Nrk was significantly reduced in regions of neointimal formation caused by guide-wire carotid artery injuries in mice, as well as in human atherosclerotic tissues, when compared to normal vessels. We identified that expression of matrix metalloproteinases (MMP3, MMP8 and MMP12) and inflammatory cytokines/chemokines (CCL6, CCL8, CCL11, CXCL1, CXCL3, CXCL5 and CXCL9) are synergistically induced by Nrk siRNA in LPS-treated mouse VSMCs. Moreover, we found that resveratrol significantly impaired LPS- and Nrk siRNA-induced expression of MMP3, CCL8, CCL11, CXCL3 and CXCL5. These results suggested that Nrk may play important roles in regulating pathological progression of atherosclerosis or neointimal- hyperplasia-related vascular diseases.