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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 1, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp177
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells

Koichi Sugimoto1, Toshiyuki Ishibashi1,*, Tatsuya Sawamura2, Nobutaka Inoue2, Masashi Kamioka1, Hironori Uekita1, Hiroshi Ohkawara1, Takayuki Sakamoto1, Nobuo Sakamoto1, Yasuo Okamoto3, Yoh Takuwa3, Akemi Kakino2, Yoshiko Fujita2, Takeshi Tanaka4, Tamio Teramoto5, Yukio Maruyama1,6 and Yasuchika Takeishi1

1 First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan
2 Department of Bioscience, National Cardiovascular Center Research Institute, Osaka, Japan
3 Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Japan
4 International Researchand Educational Institute for Integrated Medical Sciences, Tokyo Women's University, Tokyo, Japan
5 Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
6 Hoshi General Hospital

* Corresponding author. Toshiyuki Ishibashi, M.D., PhD, 1 Hikarigaoka, Fukushima 960-1295, Japan, Tel: 81-24-547-1190; fax: 81-24-548-1821, E-mail address: masaishi{at}fmu.ac.jp

Aims: RhoA and Rac1 activation plays a key role in endothelial dysfunction. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells (ECs). Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be involved in atherogenesis. This study was conducted to investigate the role of the LOX-1-MT1-MMP axis in RhoA and Rac1 activation in response to ox-LDL in ECs.

Methods and results: Ox-LDL induced rapid RhoA and Rac1 activation as well as MT1-MMP activity in cultured human aortic ECs. Inhibition of LOX-1 prevented ox-LDL-dependent RhoA and Rac1 activation. Knockdown of MT1-MMP by small interfering RNA prevented ox-LDL-induced RhoA and Rac1 activation, indicating that MT1-MMP is upstream of RhoA and Rac1. Fluorescent immunostaining revealed the colocalization of LOX-1 and MT1-MMP, and the formation of a complex of LOX-1 with MT1-MMP was detected by immunoprecipitation. Blockade of LOX-1 or MT1-MMP prevented RhoA-dependent endothelial NO synthase protein downregulation and cell invasion, Rac1-mediated NADPH oxidase activity and reactive oxygen species generation.

Conclusions: The present study provides evidence that the LOX-1-MT1-MMP axis plays a crucial role in RhoA and Rac1 activation signaling pathways in ox-LDL stimulation, suggesting that this axis may be a promising target for treating endothelial dysfunction.

KEYWORDS LOX-1; MT1-MMP; RhoA; Rac1; Endothelial dysfunction

Time for primary review: 25 Days


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