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Cardiovascular Research 2005 67(4):714-722; doi:10.1016/j.cardiores.2005.04.017
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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


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