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

Yi-Jhu Lu,Shu-Man Liang,Lujen Chen,Yee-Jee Jan,Chih-Hui Chin,Bor-Sheng Ko,Jun-Yang Liou,Cheng-Chin Kuo,Shaw-Fang Yet,Chih-Cheng Wu

doi:10.18632/aging.103104

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.

Highlights

Atherosclerosis or neointimal hyperplasia refers to a pathological process of tunica intima thickening due to the proliferation and migration of vascular smooth muscle cells (VSMCs)
To investigate whether Nik-related kinase (Nrk) is expressed in vascular cells, we examined the expression of mouse Nrk and human Nrk by western blot analysis of mouse VSMCs, rat VSMCs (A10, rVSMCs), human VSMCs, human umbilical vein endothelial cells (HUVECs), human coronary artery endothelial cells (HCAECs), human pulmonary artery endothelial cells (HPAECs), C2C12 and A549 cells
Expression of Nrk was abundant in mouse VSMCs (mVSMCs), mid-range in human VSMCs (hVSMCs) and C2C12 cells, and low in rVSMCs, HUVECs, HCAECs and HPAECs (Figure 1A)

Summary

Introduction

Atherosclerosis or neointimal hyperplasia refers to a pathological process of tunica intima thickening due to the proliferation and migration of vascular smooth muscle cells (VSMCs). Elevated expression of MMPs in www.aging-us.com vulnerable regions can be induced by cytokines in human atherosclerotic plaques [9, 10]. Nrk was first cloned from mice, and was initially detected in skeletal muscle during mouse embryogenesis [11]. Other than embryonic skeletal muscle and trophoblasts, Nrk is potentially expressed in human brain [16]. We aimed to assess the expression of Nrk in VSMCs, investigate its potential roles in regulating vascular inflammation, as well as elucidate clinical associations involving Nrk in atherosclerotic patients

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