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. 2009 Oct 1;84(1):127-36.
doi: 10.1093/cvr/cvp177. Epub 2009 Jun 1.

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

Koichi Sugimoto  1 , Toshiyuki Ishibashi, Tatsuya Sawamura, Nobutaka Inoue, Masashi Kamioka, Hironori Uekita, Hiroshi Ohkawara, Takayuki Sakamoto, Nobuo Sakamoto, Yasuo Okamoto, Yoh Takuwa, Akemi Kakino, Yoshiko Fujita, Takeshi Tanaka, Tamio Teramoto, Yukio Maruyama, Yasuchika Takeishi
Affiliations

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

Koichi Sugimoto et al. Cardiovasc Res. .

Abstract

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.

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