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

• Published in: Cardiovascular research Vol. 84; no. 1; pp. 127 - 136
• Main Authors: Sugimoto, Koichi, Ishibashi, Toshiyuki, Sawamura, Tatsuya, Inoue, Nobutaka, Kamioka, Masashi, Uekita, Hironori, Ohkawara, Hiroshi, Sakamoto, Takayuki, Sakamoto, Nobuo, Okamoto, Yasuo, Takuwa, Yoh, Kakino, Akemi, Fujita, Yoshiko, Tanaka, Takeshi, Teramoto, Tamio, Maruyama, Yukio, Takeishi, Yasuchika
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-10-2009
• Subjects: Biological and medical sciences; Cardiology. Vascular system; Cells, Cultured; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial dysfunction; Humans; Lipoproteins, LDL - toxicity; LOX-1; Matrix Metalloproteinase 14 - physiology; Medical sciences; MT1-MMP; NADPH Oxidases - physiology; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - genetics; Rac1; rac1 GTP-Binding Protein - physiology; Reactive Oxygen Species - metabolism; RhoA; rhoA GTP-Binding Protein - physiology; Scavenger Receptors, Class E - physiology; Signal Transduction - physiology; Endothelial dysfunction; MT1-MMP; Rac1; LOX-1; RhoA; Endothelial cell; Activation; Lipoprotein; Density; Phlebology; Low; Circulatory system; Cardiology; Axis
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvp177

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