Journal of Molecular Medicine

, Volume 86, Issue 6, pp 673–678 | Cite as

New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone

  • Catherine A. Lemarié
  • Pierre Paradis
  • Ernesto L. Schiffrin
Review
First Online:
Received:
Revised:
Accepted:

Abstract

Angiotensin II (Ang II) is considered the main final mediator of the renin–angiotensin–aldosterone system (RAAS). The actions of Ang II have been implicated in many cardiovascular conditions, such as hypertension, atherosclerosis, coronary heart disease, restenosis after injury, and heart failure. The Ang II type 1 receptor (AT1R), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of Ang II. This receptor is predominantly expressed in cardiovascular cells, such as vascular smooth muscle cells where it activates various signaling cascades leading to vascular remodeling and inflammation. Besides Ang II, aldosterone has emerged as an important component and mediator of the effects of the RAAS. Aldosterone-induced genomic effects mediated through binding to the mineralocorticoid receptor (MR), a member of the steroid hormone receptor superfamily, which functions as a ligand-dependent transcription factor, are characterized by a delay of minutes to hours corresponding to a long series of subcellular events that include gene activation and protein synthesis. Besides its well-known genomic actions, there is evidence of aldosterone-mediated rapid effects which lead to the activation of ion channels and other signaling pathways. Some of the effects of aldosterone occur through similar pathways as Ang II-induced signaling events. Indeed, recent studies suggest complex interactions between Ang II and aldosterone: it has become evident that aldosterone may influence the signaling or trafficking of the AT1R. Thus, growing evidence demonstrates the existence of cross-talk between Ang II and aldosterone which could potentially modulate Ang II signal transduction. These interactions between Ang II and aldosterone activate specific signaling pathways, sometimes in ways distinct from those that they induce on their own, one which may lead to pathogenic effects on target organs. Here we focus on recent findings and concepts that suggest the existence of novel signaling mechanisms whereby the cross-talk between Ang II and aldosterone plays a role in cardiovascular disease. We also discuss the importance of investigating Ang II/aldosterone cross-talk as a mean of developing new therapeutic strategies to combat cardiovascular disease.

Keywords

Angiotensin II Aldosterone Mineralocorticoid Signaling Cross-talk Hypertension Cardiovascular diseases 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The work of the authors was supported by the Canadian Institutes of Health Research (CIHR) grants 37917 and 82790, and a Canada Research Chair on Hypertension and Vascular Research (to E.L.S.), and fellowships from “Fondation pour la Recherche Médicale” and from Heart and Stroke Foundation of Canada (C.A.L).

References

  1. 1.
    Touyz RM, Schiffrin EL (2000) Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 52:639–672PubMedGoogle Scholar
  2. 2.
    Yan C, Kim D, Aizawa T, Berk BC (2003) Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator. Arterioscler Thromb Vasc Biol 23:26–36PubMedCrossRefGoogle Scholar
  3. 3.
    Pueyo ME, Arnal e, Rami J, Michel JB (1998) Angiotensin II stimulates the production of NO and peroxynitrite in endothelial cells. Am J Physiol 274:C214–220PubMedGoogle Scholar
  4. 4.
    Mehta PK, Griendling KK (2007) Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 292:C82–97PubMedCrossRefGoogle Scholar
  5. 5.
    Touyz RM, Schiffrin EL (2004) Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 122:339–352PubMedCrossRefGoogle Scholar
  6. 6.
    Mogi M, Iwai M, Horiuchi M (2007) Emerging concepts of regulation of angiotensin II receptors: new players and targets for traditional receptors. Arterioscler Thromb Vasc Biol 27:2532–2539PubMedCrossRefGoogle Scholar
  7. 7.
    Williams GH (2005) Cardiovascular benefits of aldosterone receptor antagonists: what about potassium? Hypertension 46:265–266PubMedCrossRefGoogle Scholar
  8. 8.
    Funder J (2001) Mineralocorticoids and cardiac fibrosis: the decade in review. Clin Exp Pharmacol Physiol 28:1002–1006PubMedCrossRefGoogle Scholar
  9. 9.
    Adler GK, Williams GH (2007) Aldosterone: villain or protector? Hypertension 50:31–32PubMedCrossRefGoogle Scholar
  10. 10.
    Rogerson FM, Fuller PJ (2000) Mineralocorticoid action. Steroids 65:61–73PubMedCrossRefGoogle Scholar
  11. 11.
    Fejes-Toth G, Pearce D, Naray-Fejes-Toth A (1998) Subcellular localization of mineralocorticoid receptors in living cells: effects of receptor agonists and antagonists. Proc Natl Acad Sci U S A 95:2973–2978PubMedCrossRefGoogle Scholar
  12. 12.
    Oberleithner H, Ludwig T, Riethmuller C, Hillebrand U, Albermann L, Schafer C, Shahin V, Schillers H (2004) Human endothelium: target for aldosterone. Hypertension 43:952–956PubMedCrossRefGoogle Scholar
  13. 13.
    Krug AW, Grossmann C, Schuster C, Freudinger R, Mildenberger S, Govindan MV, Gekle M (2003) Aldosterone stimulates epidermal growth factor receptor expression. J Biol Chem 278:43060–43066PubMedCrossRefGoogle Scholar
  14. 14.
    Callera GE, Touyz RM, Tostes RC, Yogi A, He Y, Malkinson S, Schiffrin EL (2005) Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src. Hypertension 45:773–779PubMedCrossRefGoogle Scholar
  15. 15.
    Ishizawa K, Izawa Y, Ito H, Miki C, Miyata K, Fujita Y, Kanematsu Y, Tsuchiya K, Tamaki T, Nishiyama A, Yoshizumi M (2005) Aldosterone stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation. Hypertension 46:1046–1052PubMedCrossRefGoogle Scholar
  16. 16.
    Krug AW, Schuster C, Gassner B, Freudinger R, Mildenberger S, Troppmair J, Gekle M (2002) Human epidermal growth factor receptor-1 expression renders Chinese hamster ovary cells sensitive to alternative aldosterone signaling. J Biol Chem 277:45892–45897PubMedCrossRefGoogle Scholar
  17. 17.
    Braun S, Losel R, Wehling M, Boldyreff B (2004) Aldosterone rapidly activates Src kinase in M-1 cells involving the mineralocorticoid receptor and HSP84. FEBS Lett 570:69–72PubMedCrossRefGoogle Scholar
  18. 18.
    Grossmann C, Benesic A, Krug AW, Freudinger R, Mildenberger S, Gassner B, Gekle M (2005) Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol Endocrinol 19:1697–1710PubMedCrossRefGoogle Scholar
  19. 19.
    Touyz RM (2003) Recent advances in intracellular signalling in hypertension. Curr Opin Nephrol Hypertens 12:165–174PubMedCrossRefGoogle Scholar
  20. 20.
    Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL (2002) Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 40:504–510PubMedCrossRefGoogle Scholar
  21. 21.
    Schiffrin EL, Gutkowska J, Genest J (1984) Effect of angiotensin II and deoxycorticosterone infusion on vascular angiotensin II receptors in rats. Am J Physiol 246:H608–614PubMedGoogle Scholar
  22. 22.
    Schiffrin EL, Franks DJ, Gutkowska J (1985) Effect of aldosterone on vascular angiotensin II receptors in the rat. Can J Physiol Pharmacol 63:1522–1527PubMedGoogle Scholar
  23. 23.
    Ullian ME, Fine JJ (1994) Mechanisms of enhanced angiotensin II-stimulated signal transduction in vascular smooth muscle by aldosterone. J Cell Physiol 161:201–208PubMedCrossRefGoogle Scholar
  24. 24.
    Harada E, Yoshimura M, Yasue H, Nakagawa O, Nakagawa M, Harada M, Mizuno Y, Nakayama M, Shimasaki Y, Ito T, Nakamura S, Kuwahara K, Saito Y, Nakao K, Ogawa H (2001) Aldosterone induces angiotensin-converting-enzyme gene expression in cultured neonatal rat cardiocytes. Circulation 104:137–139PubMedGoogle Scholar
  25. 25.
    Mazak I, Fiebeler A, Muller DN, Park JK, Shagdarsuren E, Lindschau C, Dechend R, Viedt C, Pilz B, Haller H, Luft FC (2004) Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation 109:2792–2800PubMedCrossRefGoogle Scholar
  26. 26.
    Xiao F, Puddefoot JR, Vinson GP (2000) Aldosterone mediates angiotensin II-stimulated rat vascular smooth muscle cell proliferation. J Endocrinol 165:533–536PubMedCrossRefGoogle Scholar
  27. 27.
    Min LJ, Mogi M, Li JM, Iwanami J, Iwai M, Horiuchi M (2005) Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ Res 97:434–442PubMedCrossRefGoogle Scholar
  28. 28.
    Michel F, Ambroisine ML, Duriez M, Delcayre C, Levy BI, Silvestre JS (2004) Aldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathway. Circulation 109:1933–1937PubMedCrossRefGoogle Scholar
  29. 29.
    Jaffe IZ, Mendelsohn ME (2005) Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 96:643–650PubMedCrossRefGoogle Scholar
  30. 30.
    Min LJ, Mogi M, Iwanami J, Li JM, Sakata A, Fujita T, Tsukuda K, Iwai M, Horiuchi M (2007) Cross-talk between aldosterone and angiotensin II in vascular smooth muscle cell senescence. Cardiovasc Res 76:506–516PubMedCrossRefGoogle Scholar
  31. 31.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717PubMedCrossRefGoogle Scholar
  32. 32.
    Kambara A, Holycross BJ, Wung P, Schanbacher B, Ghosh S, McCune SA, Bauer JA, Kwiatkowski P (2003) Combined effects of low-dose oral spironolactone and captopril therapy in a rat model of spontaneous hypertension and heart failure. J Cardiovasc Pharmacol 41:830–837PubMedCrossRefGoogle Scholar
  33. 33.
    Tanabe A, Naruse M, Hara Y, Sato A, Tsuchiya K, Nishikawa T, Imaki T, Takano K (2004) Aldosterone antagonist facilitates the cardioprotective effects of angiotensin receptor blockers in hypertensive rats. J Hypertens 22:1017–1023PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Catherine A. Lemarié
    • 1
    • 2
  • Pierre Paradis
    • 1
    • 2
  • Ernesto L. Schiffrin
    • 1
    • 2
  1. 1.Hypertension and Vascular Research Unit, Lady Davis Institute for Medical ResearchSir Mortimer B. Davis-Jewish General HospitalMontrealCanada
  2. 2.Department of Medicine, Sir Mortimer B. Davis-Jewish General HospitalMcGill UniversityMontrealCanada

Personalised recommendations