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
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
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
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
protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1
protein expression, and PAI-1 gene expression.
Conclusion: Induction of HIF-1
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
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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