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

نویسندگان

  • Koichi Sugimoto
  • 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
چکیده

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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عنوان ژورنال:
  • Cardiovascular research

دوره 84 1  شماره 

صفحات  -

تاریخ انتشار 2009