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

doi:10.1016/j.cardiores.2005.04.017

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

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

Hiroko Sato^a^,b, Mahito Sato^a, Hiroyoshi Kanai^a, Tsuyoshi Uchiyama^a, Tatsuya Iso^a, Yoshio Ohyama^a, Hironosuke Sakamoto^b, Junichi Tamura^b, Ryozo Nagai^c and Masahiko Kurabayashi^a^,*

^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 behypoxic because of poor perfusion. In this study, we tested(a) whether reactive oxygen species (ROS) and c-Src play rolesin hypoxic induction of HIF-1 ${alpha}$ protein and PAI-1 gene expressionin the rabbit aortic smooth muscle cell line C2/2 cells andprimary 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 increasedH₂O₂ generation, c-Src phosphorylation, HIF-1 ${alpha}$ protein expression,and PAI-1 gene expression. Catalase, a scavenger of H₂O₂, inhibitedthe hypoxia-induced ROS generation and PAI-1 gene expression.Src kinase inhibitors PP1 and PP2 inhibited hypoxia-inducedHIF-1 ${alpha}$ protein and PAI-1 gene expression. Ablation of mitochondrialrespiration by rotenone abolished hypoxia-induced ROS generation,c-Src phosphorylation, HIF-1 ${alpha}$ protein expression, and PAI-1 geneexpression.

Conclusion: Induction of HIF-1 ${alpha}$ protein and PAI-1 gene expressionin response to hypoxia was regulated by ROS production and c-Srcactivation in vascular smooth muscle cells. Mitochondria linkedthe hypoxic signal to c-Src, which in turn led to HIF-1 ${alpha}$ proteinand PAI-1 gene expression. These results provide evidence thathypoxia induces the ROS-mediated and c-Src-dependent signalingcascades which are closely associated with angiogenesis andthrombosis in atherosclerotic vasculature.

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

Time for primary review 24 days

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