PMID- 30884801 OWN - NLM STAT- MEDLINE DCOM- 20190708 LR - 20200225 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 6 DP - 2019 Mar 16 TI - ROCK2 Regulates Monocyte Migration and Cell to Cell Adhesion in Vascular Endothelial Cells. LID - 10.3390/ijms20061331 [doi] LID - 1331 AB - 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 IkappaBalpha and inhibited NF-kappaB 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. FAU - Takeda, Yusuke AU - Takeda Y AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. ms05-takeda@jikei.ac.jp. FAU - Matoba, Keiichiro AU - Matoba K AUID- ORCID: 0000-0003-0041-0483 AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. matoba@jikei.ac.jp. FAU - Kawanami, Daiji AU - Kawanami D AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. daijika@jikei.ac.jp. FAU - Nagai, Yosuke AU - Nagai Y AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. y.nagai@jikei.ac.jp. FAU - Akamine, Tomoyo AU - Akamine T AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. akamine-tm@igakuken.or.jp. FAU - Ishizawa, Sho AU - Ishizawa S AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. ishizawa@jikei.ac.jp. FAU - Kanazawa, Yasushi AU - Kanazawa Y AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. yasu@jikei.ac.jp. FAU - Yokota, Tamotsu AU - Yokota T AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. yokotat@jikei.ac.jp. FAU - Utsunomiya, Kazunori AU - Utsunomiya K AD - Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan. kazu-utsunomiya@jikei.ac.jp. LA - eng GR - N/A/Uehara Memorial Foundation/ GR - N/A/Japan Diabetes Foundation/ GR - N/A/Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care/ GR - N/A/Japan Society for the Promotion of Science/ GR - N/A/Yokoyama Foundation/ GR - N/A/MSD Life Science Foundation/ PT - Journal Article DEP - 20190316 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (CCL2 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (E-Selectin) RN - 0 (Lysophospholipids) RN - 0 (RELA protein, human) RN - 0 (Transcription Factor RelA) RN - EC 2.7.11.1 (ROCK1 protein, human) RN - EC 2.7.11.1 (ROCK2 protein, human) RN - EC 2.7.11.1 (rho-Associated Kinases) RN - EC 2.7.11.10 (I-kappa B Kinase) RN - PG6M3969SG (lysophosphatidic acid) SB - IM MH - Actin Cytoskeleton/drug effects/genetics MH - Active Transport, Cell Nucleus/drug effects MH - Aorta/cytology/metabolism MH - Atherosclerosis/*genetics/metabolism/pathology MH - Cell Adhesion/genetics MH - Cell Movement/drug effects MH - Chemokine CCL2/genetics MH - E-Selectin/genetics MH - Endothelial Cells/*drug effects/metabolism MH - Gene Expression Regulation/drug effects MH - Humans MH - I-kappa B Kinase/genetics MH - Lysophospholipids/*pharmacology MH - Monocytes/drug effects MH - Phosphorylation MH - Signal Transduction/drug effects MH - Transcription Factor RelA/genetics MH - rho-Associated Kinases/*genetics/metabolism PMC - PMC6471293 OTO - NOTNLM OT - ROCK2 OT - Rho-kinase OT - atherosclerosis OT - endothelial function OT - inflammation COIS- The authors declare no conflict of interest. EDAT- 2019/03/20 06:00 MHDA- 2019/07/10 06:00 PMCR- 2019/03/01 CRDT- 2019/03/20 06:00 PHST- 2019/02/26 00:00 [received] PHST- 2019/03/11 00:00 [revised] PHST- 2019/03/12 00:00 [accepted] PHST- 2019/03/20 06:00 [entrez] PHST- 2019/03/20 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2019/03/01 00:00 [pmc-release] AID - ijms20061331 [pii] AID - ijms-20-01331 [pii] AID - 10.3390/ijms20061331 [doi] PST - epublish SO - Int J Mol Sci. 2019 Mar 16;20(6):1331. doi: 10.3390/ijms20061331.