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Published on: July 5, 2017
Fluvastatin protects vascular smooth muscle cells against oxidative stress through the Nrf2-dependent antioxidant
Shin Makabe1, Yoichiro Takahashi, Hiroyuki Watanabe
1Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondoh, Akita 010-8543, Japan.
Objective:
HMG-CoA reductase inhibitors (statins) have pleiotropic actions, including the ability to reduce vascular oxidative stress. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in statin-mediated antioxidant effects in vascular smooth muscle cells.
Methods And Results:
In cultured human coronary artery smooth muscle cells (hCASMCs), fluvastatin activated the nuclear translocation of Nrf2, as evaluated by Western blotting and immunocytochemical analyses. Nrf2-antioxidant response element (ARE) activity was measured with a luciferase assay after transfection of reporter plasmids containing AREs. Fluvastatin significantly increased the transcriptional activity of the ARE. Electromobility shift assays using an ARE probe detected a complex that was significantly increased in intensity by fluvastatin. Western blotting and luciferase assay revealed fluvastatin activated Nrf2 via the PI3K/Akt pathway. Statins upregulated the Nrf2-related antioxidant genes heme oxygenase-1, NAD(P)H quinone oxidoreductase-1, and glutamate-cysteine ligase modifier subunits. Inhibition of Nrf2 by siRNA reduced statin-induced upregulation of these antioxidant genes. Moreover, Nrf2 siRNA markedly reduced the cytoprotective effects of fluvastatin against H(2)O(2) administration in hCASMCs.
Conclusions:
Fluvastatin exerts cytoprotective effects against oxidative stress, inducing antioxidant genes through Nrf2/ARE in hCASMCs. These results suggest that the Nrf2/ARE pathway plays an important role in the regulation of statin-mediated antioxidant effects in vascular smooth muscle cells.
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