Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

A Corrigendum to this article was published on 01 September 2009

This article has been updated

Abstract

Hyperaldosteronism is associated with impaired vascular reactivity; however, the mechanisms by which aldosterone promotes endothelial dysfunction remain unknown. Glucose-6-phosphate dehydrogenase (G6PD) modulates vascular function by limiting oxidant stress to preserve bioavailable nitric oxide (NO). Here we show that aldosterone (10−9–;10−7 mol/l) decreased endothelial G6PD expression and activity in vitro, resulting in increased oxidant stress and decreased NO levels—similar to what is observed in G6PD-deficient endothelial cells. Aldosterone decreased G6PD expression by increasing expression of the cyclic AMP−response element modulator (CREM) to inhibit cyclic AMP−response element binding protein (CREB)-mediated G6PD transcription. In vivo, infusion of aldosterone decreased vascular G6PD expression and impaired vascular reactivity. These effects were abrogated by spironolactone or vascular gene transfer of G6pd. These findings demonstrate that aldosterone induces a G6PD-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6PD activity.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Aldosterone decreases G6PD expression and activity.
Figure 2: Aldosterone decreases G6PD by increasing CREM levels.
Figure 3: Aldosterone increases endothelial cell oxidant stress and decreases bioavailable NO.
Figure 4: Effects of aldosterone on G6PD activity in vivo.
Figure 5: Aldosterone impairs vascular reactivity.
Figure 6: Spironolactone increases G6PD expression and activity to improve vascular reactivity.

Change history

  • 04 September 2009

    In the version of this article initially published, the number of one of the grants listed in the Acknowledgments was incorrect; ‘HL55993’ should have been ‘P01 HL81587’. The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Blacher, J. et al. Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension. Am. J. Hypertens. 10, 1326–1334 (1997).

    CAS  Article  Google Scholar 

  2. 2

    Duprez, D.A. et al. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur. Heart J. 19, 1371–1376 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Weber, K.T. Aldosteronism revisited: perspectives on less well-recognized actions of aldosterone. J. Lab. Clin. Med. 142, 71–82 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Farquharson, C.A. & Struthers, A.D. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 101, 594–597 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Struthers, A.D. Aldosterone-induced vasculopathy. Mol. Cell. Endocrinol. 217, 239–241 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Leopold, J.A., Cap, A., Scribner, A.W., Stanton, R.C. & Loscalzo, J. Glucose-6-phosphate dehydrogenase deficiency promotes endothelial oxidant stress and decreases endothelial nitric oxide bioavailability. FASEB J. 15, 1771–1773 (2001).

    CAS  Article  Google Scholar 

  7. 7

    Leopold, J.A., Zhang, Y.Y., Scribner, A.W., Stanton, R.C. & Loscalzo, J. Glucose-6-phosphate dehydrogenase overexpression decreases endothelial cell oxidant stress and increases bioavailable nitric oxide. Arterioscler. Thromb. Vasc. Biol. 23, 411–417 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Criss, W.E. & McKerns, K.W. Inhibitors of the catalytic activity of bovine adrenal glucose-6- phosphate dehydrogenase. Biochim. Biophys. Acta 184, 486–494 (1969).

    CAS  Article  Google Scholar 

  9. 9

    Liew, C.C. & Gornall, A.G. Effects of aldosterone on blood pressure and glucose-6-phosphate dehydrogenase activity of heart muscle. Can. J. Physiol. Pharmacol. 47, 193–197 (1969).

    CAS  Article  Google Scholar 

  10. 10

    Xu, Y., Osborne, B.W. & Stanton, R.C. Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which contributes to oxidative stress in rat kidney cortex. Am. J. Physiol. Renal Physiol. 289, F1040–F1047 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Guo, L., Zhang, Z., Green, K. & Stanton, R.C. Suppression of interleukin-1 beta-induced nitric oxide production in RINm5F cells by inhibition of glucose-6-phosphate dehydrogenase. Biochemistry 41, 14726–14733 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Macho, B. & Sassone-Corsi, P. Functional analysis of transcription factors CREB and CREM. Methods Enzymol. 370, 396–415 (2003).

    CAS  Article  Google Scholar 

  13. 13

    Zhang, X. et al. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc. Natl. Acad. Sci. USA 102, 4459–4464 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Manna, P.R. et al. Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Mol. Endocrinol. 16, 184–199 (2002).

    CAS  Article  Google Scholar 

  15. 15

    Klatt, P. et al. Characterization of heme-deficient neuronal nitric-oxide synthase reveals a role for heme in subunit dimerization and binding of the amino acid substrate and tetrahydrobiopterin. J. Biol. Chem. 271, 7336–7342 (1996).

    CAS  Article  Google Scholar 

  16. 16

    Cai, S., Khoo, J., Mussa, S., Alp, N.J. & Channon, K.M. Endothelial nitric oxide synthase dysfunction in diabetic mice: importance of tetrahydrobiopterin in eNOS dimerisation. Diabetologia 48, 1933–1940 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Leopold, J.A. et al. Glucose-6-phosphate dehydrogenase modulates vascular endothelial growth factor-mediated angiogenesis. J. Biol. Chem. 278, 32100–32106 (2003).

    CAS  Article  Google Scholar 

  18. 18

    Ding, H. et al. Endothelial dysfunction in the streptozotocin-induced diabetic apoE-deficient mouse. Br. J. Pharmcol. 146, 1110–1118 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Rousseau, M.F. et al. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J. Am. Coll. Cardiol. 40, 1596–1601 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Silvestre, J.S. et al. Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J. Biol. Chem. 273, 4883–4891 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Weber, K.T. Aldosterone in congestive heart failure. N. Engl. J. Med. 345, 1689–1697 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Massaad, C., Houard, N., Lombes, M. & Barouki, R. Modulation of human mineralocorticoid receptor function by protein kinase A. Mol. Endocrinol. 13, 57–65 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Booth, R.E., Johnson, J.P. & Stockand, J.D. Aldosterone. Adv. Physiol. Educ. 26, 8–20 (2002).

    Article  Google Scholar 

  24. 24

    Mioduszewska, B., Jaworski, J. & Kaczmarek, L. Inducible cAMP early repressor (ICER) in the nervous system–a transcriptional regulator of neuronal plasticity and programmed cell death. J. Neurochem. 87, 1313–1320 (2003).

    CAS  Article  Google Scholar 

  25. 25

    Boissel, J.P., Bros, M., Schrock, A., Godtel-Armbrust, U. & Forstermann, U. Cyclic AMP-mediated upregulation of the expression of neuronal NO synthase in human A673 neuroepithelioma cells results in a decrease in the level of bioactive NO production: analysis of the signaling mechanisms that are involved. Biochemistry 43, 7197–7206 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Shepard, J.D., Liu, Y., Sassone-Corsi, P. & Aguilera, G. Role of glucocorticoids and cAMP-mediated repression in limiting corticotropin-releasing hormone transcription during stress. J. Neurosci. 25, 4073–4081 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Ding, B. et al. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc. Natl. Acad. Sci. USA 102, 14771–14776 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Nagata, D. et al. Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension 48, 165–171 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Sun, Y. et al. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am. J. Pathol. 161, 1773–1781 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Schafer, A. et al. Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction. Cardiovasc. Res. 58, 655–662 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Matsui, R. et al. Glucose-6 phosphate dehydrogenase deficiency decreases the vascular response to angiotensin II. Circulation 112, 257–263 (2005).

    CAS  Article  Google Scholar 

  32. 32

    Nishizaka, M.K., Zaman, M.A., Green, S.A., Renfroe, K.Y. & Calhoun, D.A. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation 109, 2857–2861 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Abiose, A.K. et al. Effect of spironolactone on endothelial function in patients with congestive heart failure on conventional medical therapy. Am. J. Card. 93, 1564–1566 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Macdonald, J.E., Kennedy, N. & Struthers, A.D. Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment. Heart 90, 765–770 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Davies, J.I., Band, M., Morris, A. & Struthers, A.D. Spironolactone impairs endothelial function and heart rate variability in patients with type 2 diabetes. Diabetologia 47, 1687–1694 (2004).

    CAS  Article  Google Scholar 

  36. 36

    Zhang, Z., Apse, K., Pang, J. & Stanton, R.C. High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J. Biol. Chem. 275, 40042–40047 (2000).

    CAS  Article  Google Scholar 

  37. 37

    Garnier, A. et al. Cardiac specific increase in aldosterone production induces coronary dysfunction in aldosterone synthase-transgenic mice. Circulation 110, 1819–1825 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Forgione, M.A. et al. The A326G (A+) variant of the glucose-6-phosphate dehydrogenase gene is associated with endothelial dysfunction in African Americans. J. Am. Coll. Cardiol. 41, 249A (2003).

    Article  Google Scholar 

  39. 39

    Leopold, J.A. & Loscalzo, J. Cyclic strain modulates resistance to oxidant stress by increasing G6PDH expression in smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 279, H2477–H2485 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Zhang, Y.Y. et al. Expression of 5-lipoxygenase in pulmonary artery endothelial cells. Biochem. J. 361, 267–276 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Dong, Q.G. et al. A general strategy for isolation of endothelial cells from murine tissues. Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants. Arterioscler. Thromb. Vasc. Biol. 17, 1599–1604 (1997).

    CAS  Article  Google Scholar 

  42. 42

    Zhang, Z., Yu, J. & Stanton, R.C. A method for determination of pyridine nucleotides using a single extract. Anal. Biochem. 285, 163–167 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Zhang, M.X. et al. Regulation of endothelial nitric oxide synthase by small RNA. Proc. Natl. Acad. Sci. USA 102, 16967–16972 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Uittenbogaard, A., Shaul, P.W., Yuhanna, I.S., Blair, A. & Smart, E.J. High density lipoprotein prevents oxidized low density lipoprotein-induced inhibition of endothelial nitric-oxide synthase localization and activation in caveolae. J. Biol. Chem. 275, 11278–11283 (2000).

    CAS  Article  Google Scholar 

  45. 45

    Hou, J., Speirs, H.J., Seckl, J.R. & Brown, R.W. Sgk1 gene expression in kidney and its regulation by aldosterone: spatio-temporal heterogeneity and quantitative analysis. J. Am. Soc. Nephrol. 13, 1190–1198 (2002).

    CAS  Article  Google Scholar 

  46. 46

    Michel, F. et al. Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway. Circulation 109, 1933–1937 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Eberhardt, R.T. et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J. Clin. Invest. 106, 483–491 (2000).

    CAS  Article  Google Scholar 

  48. 48

    Virdis, A. et al. Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 1352–1357 (2003).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the US National Institutes of Health (grants HL61828, HL58976, P01 HL81587, HV28178 to J.L.; HL04399 and HL081110 to J.A.L.; HL067297, HL071775 and HL073756 to R.L.; and DK053480-05 to R.C.S.) and by a Grant-in-Aid from the American Heart Association (to J.A.L.).

Author information

Affiliations

Authors

Contributions

J.A.L. designed the study, supervised the project, conducted experiments and wrote the manuscript. A.D. contributed to the in vitro and in vivo experiments. B.A.M., A.W.S., D.E.H. and R.C.S contributed to the in vitro experiments. R.L. contributed to the in vivo experiments. B.P. contributed to data interpretation. J.L. contributed to data interpretation and manuscript critique.

Corresponding author

Correspondence to Jane A Leopold.

Ethics declarations

Competing interests

B.P. is a consultant for Pfizer, Novartis, Alteon and Astra Zeneca.

Supplementary information

Supplementary Fig. 1

Aldosterone decreases G6PD expression in human coronary artery endothelial cells. (PDF 47 kb)

Supplementary Fig. 2

Aldosterone decreases G6PD expression by protein kinase A activation. (PDF 56 kb)

Supplementary Fig. 3

Inhibition of CREB or CREM expression by siRNA. (PDF 68 kb)

Supplementary Fig. 4

Aldosterone and CREB activation: upstream signaling kinases and downstream transcription factors. (PDF 73 kb)

Supplementary Fig. 5

Source of reactive oxygen species in aldosterone-treated cells. (PDF 43 kb)

Supplementary Fig. 6

Spironolactone increases G6PD activity. (PDF 28 kb)

Supplementary Fig. 7

G6PD overexpression preserves G6PD activity in vitro. (PDF 49 kb)

Supplementary Fig. 8

G6PD overexpression preserves G6PD activity in vivo. (PDF 52 kb)

Supplementary Methods (PDF 141 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Leopold, J., Dam, A., Maron, B. et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med 13, 189–197 (2007). https://doi.org/10.1038/nm1545

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing