ROCK2 Regulates Monocyte Migration and Cell to Cell Adhesion in Vascular Endothelial Cells.

Yusuke Takeda,Sho Ishizawa,Tamotsu Yokota,Tomoyo Akamine,Keiichiro Matoba,Yosuke Nagai,Daiji Kawanami,Yasushi Kanazawa,Kazunori Utsunomiya

doi:10.3390/ijms20061331

Abstract

The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and migration. A pro-inflammatory lipid mediator, lysophosphatidic acid (LPA), is a potent activator of the Rho/ROCK signalling pathway and has been shown to induce the expression of chemokines and cell adhesion molecules (CAMs). In the present study, we aimed to elucidate the precise mechanism by which ROCK regulates LPA-induced expressions and functions of chemokines and CAMs. We observed that ROCK blockade reduced LPA-induced phosphorylation of IκBα and inhibited NF-κB RelA/p65 phosphorylation, leading to attenuation of RelA/p65 nuclear translocation. Furthermore, small interfering RNA-mediated ROCK isoform knockdown experiments revealed that LPA induces the expression of monocyte chemoattractant protein-1 (MCP-1) and E-selectin via ROCK2 in human aortic endothelial cells (HAECs). Importantly, we found that ROCK2 but not ROCK1 controls LPA-induced monocytic migration and monocyte adhesion toward endothelial cells. These findings demonstrate that ROCK2 is a key regulator of endothelial inflammation. We conclude that targeting endothelial ROCK2 is potentially effective in attenuation of atherosclerosis.

Highlights

Atherosclerosis is a chronic arterial disease that is caused by inflammatory and regenerative processes
In the progression of the atherosclerosis, endothelial-leukocyte adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and E-selectin play a key role in the early adhesion of mononuclear leukocytes to arterial endothelium at sites of atheroma initiation
Lysophosphatidic acid (LPA) accumulates in atherosclerosis lesions [6,7] and it triggers the release of the chemokines including CCLs, CXCLs, colony-stimulating factors and interleukins from endothelial cells through its receptors [8,9,10]

Summary

Introduction

Atherosclerosis is a chronic arterial disease that is caused by inflammatory and regenerative processes. In the progression of the atherosclerosis, endothelial-leukocyte adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and E-selectin play a key role in the early adhesion of mononuclear leukocytes to arterial endothelium at sites of atheroma initiation. Lysophosphatidic acid (LPA), a pro-inflammatory lipid mediator, is produced and released from activated platelet [2]. LPA accumulates in atherosclerosis lesions [6,7] and it triggers the release of the chemokines including CCLs, CXCLs, colony-stimulating factors and interleukins from endothelial cells through its receptors [8,9,10]. Despite the importance of lipid mediator-induced vascular inflammation, our understanding of the molecular mechanisms that governs atherosclerosis remains incomplete. Given the epidemic of cardiovascular disease, understanding the precise mechanism regulating LPA-induced atherogenic signalling is of considerable interest

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Methods

Results