Skip to main content


We’d like to understand how you use our websites in order to improve them. Register your interest.

The mitochondria mediate the induction of NOX1 gene expression by aldosterone in an ATF-1-dependent manner


High aldosterone (Ald) levels can induce hypertrophy of vascular smooth muscle cells (VSMCs), which carries high risks of heart failure. A previous study showed that Ald induces hypertrophy of VSMCs by up-regulating NOX1, a catalytic subunit of NADPH oxidase that produces superoxides. However, the precise mechanism remains unknown. Diphenylene iodonium (DPI) is known as an inhibitor of complex I in the mitochondrial respiratory chain, and it was also found to almost completely suppress the induction of NOX1 mRNA and the phosphorylation of activating transcription factor (ATF-1) by PGF2α or PDGF in a rat VSMC cell line. In this study, we found that the Ald-induced phosphorylation of ATF-1 and NOX1 expression was significantly suppressed by DPI. Silencing of ATF-1 gene expression attenuated the induction of NOX1 mRNA expression, and over-expression of ATF-1 restored Ald-induced NOX1 expression. On the basis of this data, we show that the mitochondria mediate aldosterone-induced NOX1 gene expression in an ATF-1-dependent manner.





activating transcription factor-1


cAMP-response element


CRE-binding protein


Dulbecco’s modified Eagle’s medium


diphenylene iodonium


fetal bovine serum


Mn(III)tetrakis(4-benzoic acid)porphyrin chloride


mineralocorticoid receptor


(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide


NADPH oxidase 1


reactive oxygen species


vascular smooth muscle cell


  1. 1.

    Mazak, I., Fiebeler, A., Muller, D.N., Park, J.K., Shagdarsuren, E., Lindschau, C., Dechend, R., Viedt, C., Pilz, B., Haller, H. and Luft, F.C. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation 109 (2004) 2792–2800.

  2. 2.

    Pitt, B., Zannad, F., Remme, W.J., Cody, R., Castaigne, A., Perez, A., Palensky, J. and Wittes, J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure, randomized aldactone evaluation study investigators. N. Engl. J. Med. 341 (1999) 709–717.

  3. 3.

    Zannad, F., Ella, F., Dousset, B., Perez, A. and Pitt, B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES), Rales Investigators. Circulation 102 (2000) 2700–2706.

  4. 4.

    Irani, K. Oxidant signaling in vascular cell growth, death, and survival: a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ. Res. 87 (2000) 179–183.

  5. 5.

    Griendling, K.K., Sorescu, D. and Ushio-Fukai, M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ. Res. 86 (2000) 449–501.

  6. 6.

    Suh, Y.A., Arnold, R.S., Lassegue, B., Shi, J., Xu, X., Sorescu, D., Chung, A.B., Griendling, K.K. and Lambeth, J.D. Cell.transformation by the superoxide-generating oxidase Mox1. Nature 401 (1999) 79–82.

  7. 7.

    Lassegue, B., Sorescu, D., Szocs, K., Yin, Q., Akers, M., Zhang, Y., Grant, S.L., Lambeth, J.D. and Griendling, K.K. Griendling, Novel gp91(phox) homologues in vascular smooth muscle cells: nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ. Res. 88 (2001) 858–860.

  8. 8.

    Katsuyama, M., Fan, C., Arakawa, N., Nishinaka, T., Miyagishi, M., Taira, K. and Yabe-Nishimura, C. Essential role of ATF-1 in induction of NOX1, a catalytic subunit of NADPH oxidase: involvement of mitochondrial respiratory chain. Biochem. J. 386 (2005) 255–261.

  9. 9.

    Matsuno, K., Yamada, H., Iwata, K., Jin, D., Katsuyama, M., Matsuki, M., Takai, S., Yamanish, K., Miyazaki, M., Matsubara, H. and Yabe-Nishimur, C. A Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice. Circulation 112 (2005) 2677–2685.

  10. 10.

    Nishinaka, T. and Yabe-Nishimura, C. EGF receptor-ERK pathway is the major signaling pathway that mediates upregulation of aldose reductase expression under oxidative stress. Free Radic. Biol. Med. 31 (2001) 205–216.

  11. 11.

    Miyagishi, M. and Taira, K. U6 promoter-driven siRNAs with four uridine 3’overhangs efficiently suppress targeted gene expression in mammalian cells. Nat. Biotechnol. 20 (2002) 497–500.

  12. 12.

    Yokota, T., Sakamoto, N., Enomoto, N., Tanabe, Y., Miyagishi, M., Maekawa, S., Yi, L., Kurosaki, M., Taira, K., Watanabe, M. and Mizusawa, H. Inhibition of intracellular hepatitis C virus replication by synthetic and vector-derived small interfering RNAs. EMBO. Rep. 4 (2003) 602–608.

  13. 13.

    Li, Y. and Trush, M.A. Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. Biochem. Biophys. Res. Commun. 253 (1998) 295–299.

  14. 14.

    Montminy, M.R., Sevarino, K.A., Wagner, J.A., Mandel, G.. and Goodman, R.H. Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc. Natl. Acad. Sci. USA 83 (1986) 6682–6686.

  15. 15.

    Katsuyama, M., Fan, C. and Yabe-Nishimura, C. NADPH oxidase is involved in prostaglandin F2alpha-induced hypertrophy of vascular smooth muscle cells: induction of NOX1 by PGF2alpha. J. Biol. Chem. 277 (2002) 13438–13442.

  16. 16.

    Katsuyama, M., Cevik, M.O., Arakawa, N., Kakehi, T., Nishinaka, T., Iwata, K., Ibi, M., Matsuno K. and Nishimura, C.Y. Myocyte enhancer factor 2B is involved in the inducible expression of NOX1/NADPH oxidase, a vascular superoxide-producing enzyme. FEBS J. 274 (2007) 5128–5136.

  17. 17.

    Lee, S.B., Bae, I.H., Bae, Y.S. and Um, H.D. Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death. J. Biol. Chem. 281 (2006) 36228–36235.

  18. 18.

    Young, M. and Funder, J. Mineralocorticoid action and sodium-hydrogen exchange: studies in experimental cardiac fibrosis Endocrinology 144 (2003) 3848–3851.

  19. 19.

    Lombes, M., Oblin, M.E., Gasc, J.M., Baulieu, E.E., Farman, N. and Bonvalet, J.P. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ. Res. 71 (1992) 503–510.

  20. 20.

    Arriza, J.L., Weinberger, C., Cerelli, G., Glaser, T.M., Handelin B.L., Housman, D.E. and Evans, R.M. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237 (1987) 268–275.

  21. 21.

    Losel, R.M., Feuring, M., Falkenstein, E. and Wehling, M. Nongenomic effects of aldosterone: cellular aspects and clinical implications. Steroids 67 (2002) 493–498.

Download references

Author information



Corresponding author

Correspondence to Chunyuan Fan.

Additional information

These authors contributed equally to this work

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fu, Y., Shi, G., Wu, Y. et al. The mitochondria mediate the induction of NOX1 gene expression by aldosterone in an ATF-1-dependent manner. Cell Mol Biol Lett 16, 226–235 (2011).

Download citation

Key words

  • Aldosterone
  • Mitochondria
  • ATF-1
  • NOX1
  • VSMC