Skip Navigation

Cardiovascular Research 2005 67(4):714-722; doi:10.1016/j.cardiores.2005.04.017
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sato, H.
Right arrow Articles by Kurabayashi, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sato, H.
Right arrow Articles by Kurabayashi, M.
Social Bookmarking
 Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2005, European Society of Cardiology

Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells

Hiroko Satoa,b, Mahito Satoa, Hiroyoshi Kanaia, Tsuyoshi Uchiyamaa, Tatsuya Isoa, Yoshio Ohyamaa, Hironosuke Sakamotob, Junichi Tamurab, Ryozo Nagaic and Masahiko Kurabayashia,*

aDepartment of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan
bDepartment of General Medicine, Gunma University Hospital, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan
cCardiovascular Medicine, Graduate School of Medicine University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan

* Corresponding author. Tel.: +81 27 220 8140; fax: +81 27 220 8150. Email address: mkuraba{at}med.gunma-u.ac.jp

Objective: Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1{alpha} protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism.

Methods and results: Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1{alpha} protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1{alpha} protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1{alpha} protein expression, and PAI-1 gene expression.

Conclusion: Induction of HIF-1{alpha} protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1{alpha} protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.

KEYWORDS Atherosclerosis; Hypoxia/anoxia; Smooth muscle; Signal transduction


Time for primary review 24 days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
Am. J. Pathol.Home page
L. Llacuna, M. Mari, J. M. Lluis, C. Garcia-Ruiz, J. C. Fernandez-Checa, and A. Morales
Reactive Oxygen Species Mediate Liver Injury Through Parenchymal Nuclear Factor-{kappa}B Inactivation in Prolonged Ischemia/Reperfusion
Am. J. Pathol., May 1, 2009; 174(5): 1776 - 1785.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
D. J. Kemble and G. Sun
Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation
PNAS, March 31, 2009; 106(13): 5070 - 5075.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
G. A. Knock, V. A. Snetkov, Y. Shaifta, S. Drndarski, J. P.T. Ward, and P. I. Aaronson
Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery
Cardiovasc Res, December 1, 2008; 80(3): 453 - 462.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
J. M. Lluis, F. Buricchi, P. Chiarugi, A. Morales, and J. C. Fernandez-Checa
Dual Role of Mitochondrial Reactive Oxygen Species in Hypoxia Signaling: Activation of Nuclear Factor-{kappa}B via c-SRC and Oxidant-Dependent Cell Death
Cancer Res., August 1, 2007; 67(15): 7368 - 7377.
[Abstract] [Full Text] [PDF]


Home page
JNCI J Natl Cancer InstHome page
S. H. Oh, J. K. Woo, Y. D. Yazici, J. N. Myers, W.-Y. Kim, Q. Jin, S. S. Hong, H.-J. Park, Y.-G. Suh, K.-W. Kim, et al.
Structural Basis for Depletion of Heat Shock Protein 90 Client Proteins by Deguelin
J Natl Cancer Inst, June 20, 2007; 99(12): 949 - 961.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
K. Kappert, J. Sparwel, A. Sandin, A. Seiler, U. Siebolts, O. Leppanen, S. Rosenkranz, and A. Ostman
Antioxidants Relieve Phosphatase Inhibition and Reduce PDGF Signaling in Cultured VSMCs and in Restenosis
Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2644 - 2651.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
J. Gutierrez, S. W. Ballinger, V. M. Darley-Usmar, and A. Landar
Free Radicals, Mitochondria, and Oxidized Lipids: The Emerging Role in Signal Transduction in Vascular Cells
Circ. Res., October 27, 2006; 99(9): 924 - 932.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
Rebuttal from dr. Ward.
J Appl Physiol, September 1, 2006; 101(3): 998 - 998.
[Full Text] [PDF]


Home page
J. Biol. Chem.Home page
J. Lieskovska, Y. Ling, J. Badley-Clarke, and D. R. Clemmons
The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells
J. Biol. Chem., September 1, 2006; 281(35): 25041 - 25053.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
R. E. Clempus and K. K. Griendling
Reactive oxygen species signaling in vascular smooth muscle cells
Cardiovasc Res, July 15, 2006; 71(2): 216 - 225.
[Abstract] [Full Text] [PDF]


Home page
Mol. Biol. CellHome page
A. Pedram, M. Razandi, D. C. Wallace, and E. R. Levin
Functional Estrogen Receptors in the Mitochondria of Breast Cancer Cells
Mol. Biol. Cell, May 1, 2006; 17(5): 2125 - 2137.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
H. M. Piper and E. A. Martinson
Cardiovascular Research speeds up-Even more
Cardiovasc Res, March 1, 2006; 69(4): 773 - 776.
[Full Text] [PDF]



Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.