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LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells.
Cardiovasc Res. 2009 Oct 01; 84(1):127-36.CR

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.

Authors+Show Affiliations

First Department of Internal Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19487339

Citation

Sugimoto, Koichi, et al. "LOX-1-MT1-MMP Axis Is Crucial for RhoA and Rac1 Activation Induced By Oxidized Low-density Lipoprotein in Endothelial Cells." Cardiovascular Research, vol. 84, no. 1, 2009, pp. 127-36.
Sugimoto K, Ishibashi T, Sawamura T, et al. LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovasc Res. 2009;84(1):127-36.
Sugimoto, K., Ishibashi, T., Sawamura, T., Inoue, N., Kamioka, M., Uekita, H., Ohkawara, H., Sakamoto, T., Sakamoto, N., Okamoto, Y., Takuwa, Y., Kakino, A., Fujita, Y., Tanaka, T., Teramoto, T., Maruyama, Y., & Takeishi, Y. (2009). LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovascular Research, 84(1), 127-36. https://doi.org/10.1093/cvr/cvp177
Sugimoto K, et al. LOX-1-MT1-MMP Axis Is Crucial for RhoA and Rac1 Activation Induced By Oxidized Low-density Lipoprotein in Endothelial Cells. Cardiovasc Res. 2009 Oct 1;84(1):127-36. PubMed PMID: 19487339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. AU - Sugimoto,Koichi, AU - Ishibashi,Toshiyuki, AU - Sawamura,Tatsuya, AU - Inoue,Nobutaka, AU - Kamioka,Masashi, AU - Uekita,Hironori, AU - Ohkawara,Hiroshi, AU - Sakamoto,Takayuki, AU - Sakamoto,Nobuo, AU - Okamoto,Yasuo, AU - Takuwa,Yoh, AU - Kakino,Akemi, AU - Fujita,Yoshiko, AU - Tanaka,Takeshi, AU - Teramoto,Tamio, AU - Maruyama,Yukio, AU - Takeishi,Yasuchika, Y1 - 2009/06/01/ PY - 2009/6/3/entrez PY - 2009/6/3/pubmed PY - 2009/11/17/medline SP - 127 EP - 36 JF - Cardiovascular research JO - Cardiovasc Res VL - 84 IS - 1 N2 - 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/19487339/LOX_1_MT1_MMP_axis_is_crucial_for_RhoA_and_Rac1_activation_induced_by_oxidized_low_density_lipoprotein_in_endothelial_cells_ DB - PRIME DP - Unbound Medicine ER -