Pflügers Archiv - European Journal of Physiology

, Volume 465, Issue 12, pp 1661–1670 | Cite as

Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease

  • Amy McCurley
  • Adam McGraw
  • Dafina Pruthi
  • Iris Z. JaffeEmail author
Invited Review


The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone on renal sodium handling. In recent years, it has become clear that MR is expressed in vascular smooth muscle cells (SMCs), and interest has grown in understanding the direct role of SMC MR in regulating vascular function. This interest stems from multiple clinical studies where MR inhibitor treatment reduced the incidence of cardiovascular events and mortality. This review summarizes the most recent advances in our understanding of SMC MR in regulating normal vascular function and in promoting vascular disease. Many new studies suggest a role for SMC MR activation in stimulating vascular contraction and contributing to vessel inflammation, fibrosis, and remodeling. These detrimental vascular effects of MR activation appear to be independent of changes in blood pressure and are synergistic with the presence of endothelial dysfunction or damage. Thus, in humans with underlying cardiovascular disease or cardiovascular risk factors, SMC MR activation may promote hypertension, atherosclerosis, and vascular aging. Further exploration of the molecular mechanisms for the effects of SMC MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders.


Aldosterone Mineralocorticoid receptor (MR) Atherosclerosis Hypertension Inflammation Vascular remodeling Vascular aging 


  1. 1.
    Baker ME (2001) Adrenal and sex steroid receptor evolution: environmental implications. J Mol Endocrinol 26:119–125PubMedCrossRefGoogle Scholar
  2. 2.
    Baldo MP, Forechi L, Morra EA, Zaniqueli D, Machado RC, Lunz W, Rodrigues SL, Mill JG (2011) Long-term use of low-dose spironolactone in spontaneously hypertensive rats: effects on left ventricular hypertrophy and stiffness. Pharmacol Rep 63(4):975–982PubMedGoogle Scholar
  3. 3.
    Batterink J, Stabler SN, Tejani AM, Fowkes CT (2010) Spironolactone for hypertension. Cochrane Database Syst Rev (8):CD008169Google Scholar
  4. 4.
    Baumann M, Megens R, Bartholome R, Dolff S, van Zandvoort MA, Smits JF, Struijker-Boudier HA, De Mey JG (2007) Prehypertensive renin–angiotensin–aldosterone system blockade in spontaneously hypertensive rats ameliorates the loss of long-term vascular function. Hypertens Res 30(9):853–861PubMedCrossRefGoogle Scholar
  5. 5.
    Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P et al (2009) Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119(3):524–530PubMedCrossRefGoogle Scholar
  6. 6.
    Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Kriz W, Warth R, Greger R, Schutz G (1998) Mineralocorticoid receptor knockout mice: pathophysiology of Na + metabolism. Proc Natl Acad Sci U S A 95(16):9424–9429PubMedCrossRefGoogle Scholar
  7. 7.
    Berger S, Bleich M, Schmid W, Greger R, Schutz G (2000) Mineralocorticoid receptor knockout mice: lessons on Na + metabolism. Kidney Int 57(4):1295–1298PubMedCrossRefGoogle Scholar
  8. 8.
    Bernini G, Galetta F, Franzoni F, Bardini M, Taurino C, Bernardini M, Ghiadoni L, Bernini M, Santoro G, Salvetti A (2008) Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism. J Hypertens 26(12):2399–2405PubMedCrossRefGoogle Scholar
  9. 9.
    Bhargava A, Wang J, Pearce D (2004) Regulation of epithelial ion transport by aldosterone through changes in gene expression. Mol Cell Endocrinol 217(1–2):189–196PubMedCrossRefGoogle Scholar
  10. 10.
    Cassis P, Conti S, Remuzzi G, Benigni A (2010) Angiotensin receptors as determinants of life span. Pflugers Arch 459(2):325–332PubMedCrossRefGoogle Scholar
  11. 11.
    Chugh G, Lokhandwala MF, Asghar M (2012) Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats. Hypertension 59(5):1029–1036PubMedCrossRefGoogle Scholar
  12. 12.
    Croom KF, Perry CM (2005) Eplerenone: a review of its use in essential hypertension. Am J Cardiovasc Drugs 5(1):51–69PubMedCrossRefGoogle Scholar
  13. 13.
    Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone MA Jr (2004) Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A 101(41):14871–14876PubMedCrossRefGoogle Scholar
  14. 14.
    Deuchar GA, McLean D, Hadoke PW, Brownstein DG, Webb DJ, Mullins JJ, Chapman K, Seckl JR, Kotelevtsev YV (2011) 11β-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe−/− mice. Endocrinology 152(1):236–246PubMedCrossRefGoogle Scholar
  15. 15.
    Funder JW, Mihailidou AS (2009) Aldosterone and mineralocorticoid receptors: clinical studies and basic biology. Mol Cell Endocrinol 301(1–2):2–6PubMedCrossRefGoogle Scholar
  16. 16.
    Funder JW, Pearce PT, Smith R, Campbell J (1989) Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors. Endocrinology 125(4):2224–2226PubMedCrossRefGoogle Scholar
  17. 17.
    Gomez D, Owens GK (2012) Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc Res 95(2):156–164PubMedCrossRefGoogle Scholar
  18. 18.
    Gradman AH (2009) Role of angiotensin II type 1 receptor antagonists in the treatment of hypertension in patients aged >65 years. Drugs Aging 26(9):751–767PubMedCrossRefGoogle Scholar
  19. 19.
    Gronholdt ML, Dalager-Pedersen S, Falk E (1998) Coronary atherosclerosis: determinants of plaque rupture. Eur Heart J 19:C24–C29PubMedGoogle Scholar
  20. 20.
    Grossmann C, Krug AW, Freudinger R, Mildenberger S, Voelker K, Gekle M (2007) Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter. Am J Physiol Endocrinol Metab 292(6):E1790–E1800PubMedCrossRefGoogle Scholar
  21. 21.
    Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12(3):204–212PubMedCrossRefGoogle Scholar
  22. 22.
    Hastings NE, Feaver RE, Lee MY, Wamhoff BR, Blackman BR (2009) Human IL-8 regulates smooth muscle cell VCAM-1 expression in response to endothelial cells exposed to atheroprone flow. Arterioscler Thromb Vasc Biol 29(5):725–731PubMedCrossRefGoogle Scholar
  23. 23.
    Hillaert M, Lentjes EG, Kemperman H, van der Graaf Y, Nathoe HM, Beygui F, Montalescot G, Doevendans PA, Wassink AM, Van Belle E et al (2012) Aldosterone, atherosclerosis and vascular events in patients with stable coronary artery disease. Int J Cardiol. doi: 10.1016/j.ijcard.2012.05.034 PubMedGoogle Scholar
  24. 24.
    Hillaert MA, Lentjes EG, Beygui F, Kemperman H, Asselbergs FW, Nathoe HM, Agostoni P, Voskuil M, Ivanes F, Jude B et al (2011) Measuring and targeting aldosterone and renin in atherosclerosis—a review of clinical data. Am Heart J 162(4):585–596PubMedCrossRefGoogle Scholar
  25. 25.
    Ho-Tin-Noe B, Michel JB (2011) Initiation of angiogenesis in atherosclerosis: smooth muscle cells as mediators of the angiogenic response to atheroma formation. Trends Cardiovasc Med 21(7):183–187PubMedCrossRefGoogle Scholar
  26. 26.
    Hofmann F (2005) The biology of cyclic GMP-dependent protein kinases. J Biol Chem 280(1):1–4PubMedGoogle Scholar
  27. 27.
    Holaj R, Zelinka T, Wichterle D, Petrak O, Strauch B, Widimsky J Jr (2007) Increased intima-media thickness of the common carotid artery in primary aldosteronism in comparison with essential hypertension. J Hypertens 25(7):1451–1457PubMedCrossRefGoogle Scholar
  28. 28.
    Hyman DJ, Taffet GE (2009) Blood pressure control in the elderly: can you have too much of a good thing? Curr Hypertens Rep 11(5):337–342PubMedCrossRefGoogle Scholar
  29. 29.
    Iqbal J, Macdonald LJ, Low L, Seckl JR, Yau CW, Walker BR, Hadoke PW (2012) Contribution of endogenous glucocorticoids and their intravascular metabolism by 11beta-HSDs to postangioplasty neointimal proliferation in mice. Endocrinology 153(12):5896–5905PubMedCrossRefGoogle Scholar
  30. 30.
    Ivanes F, Susen S, Mouquet F, Pigny P, Cuilleret F, Sautiere K, Collet JP, Beygui F, Hennache B, Ennezat PV et al (2012) Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure. Eur Heart J 33(2):191–202PubMedCrossRefGoogle Scholar
  31. 31.
    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(6):643–650PubMedCrossRefGoogle Scholar
  32. 32.
    Jaffe IZ, Newfell BG, Aronovitz M, Mohammad NN, McGraw AP, Perreault RE, Carmeliet P, Ehsan A, Mendelsohn ME (2010) Placental growth factor mediates aldosterone-dependent vascular injury in mice. J Clin Invest 120(11):3891–3900PubMedCrossRefGoogle Scholar
  33. 33.
    Jaffe IZ, Tintut Y, Newfell BG, Demer LL, Mendelsohn ME (2007) Mineralocorticoid receptor activation promotes vascular cell calcification. Arterioscler Thromb Vasc Biol 27(4):799–805PubMedCrossRefGoogle Scholar
  34. 34.
    Johnson RC, Leopold JA, Loscalzo J (2006) Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res 99(10):1044–1059PubMedCrossRefGoogle Scholar
  35. 35.
    Keidar S, Hayek T, Kaplan M, Pavlotzky E, Hamoud S, Coleman R, Aviram M (2003) Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 41(6):955–963PubMedCrossRefGoogle Scholar
  36. 36.
    Keidar S, Kaplan M, Pavlotzky E, Coleman R, Hayek T, Hamoud S, Aviram M (2004) Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation 109(18):2213–2220PubMedCrossRefGoogle Scholar
  37. 37.
    Krug AW, Allenhofer L, Monticone R, Spinetti G, Gekle M, Wang M, Lakatta EG (2010) Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathways. Hypertension 55(6):1476–1483PubMedCrossRefGoogle Scholar
  38. 38.
    Lacolley P, Safar ME, Lucet B, Ledudal K, Labat C, Benetos A (2001) Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats. J Am Coll Cardiol 37(2):662–667PubMedCrossRefGoogle Scholar
  39. 39.
    Leopold JA (2009) Rapid aldosterone signaling and vascular reactivity: relax or don't do it. J Cardiovasc Pharmacol 54(6):465–467PubMedCrossRefGoogle Scholar
  40. 40.
    Levy DG, Rocha R, Funder JW (2004) Distinguishing the antihypertensive and electrolyte effects of eplerenone. J Clin Endocrinol Metab 89(6):2736–2740PubMedCrossRefGoogle Scholar
  41. 41.
    Linz W, Heitsch H, Scholkens BA, Wiemer G (2000) Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats. Hypertension 35(4):908–913PubMedCrossRefGoogle Scholar
  42. 42.
    Logan AG (2011) Hypertension in aging patients. Expert Rev Cardiovasc Ther 9(1):113–120PubMedCrossRefGoogle Scholar
  43. 43.
    Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet JP (1992) Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res 71(3):503–510PubMedCrossRefGoogle Scholar
  44. 44.
    Luo W, Meng Y, Ji HL, Pan CQ, Huang S, Yu CH, Xiao LM, Cui K, Ni SY, Zhang ZS et al (2012) Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat. PLoS One 7(3):e34230PubMedCrossRefGoogle Scholar
  45. 45.
    Luther JM, Luo P, Wang Z, Cohen SE, Kim HS, Fogo AB, Brown NJ (2012) Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury. Kidney Int 82(6):643–651PubMedCrossRefGoogle Scholar
  46. 46.
    Maron BA, Zhang YY, Handy DE, Beuve A, Tang SS, Loscalzo J, Leopold JA (2009) Aldosterone increases oxidant stress to impair guanylyl cyclase activity by cysteinyl thiol oxidation in vascular smooth muscle cells. J Biol Chem 284(12):7665–7672PubMedCrossRefGoogle Scholar
  47. 47.
    McCurley A, Jaffe IZ (2012) Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol 350(2):256–265PubMedCrossRefGoogle Scholar
  48. 48.
    McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, Chambon P, Hill MA, Dorrance AM, Mendelsohn ME, Jaffe IZ (2012) Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med 18(9):1429–1433PubMedCrossRefGoogle Scholar
  49. 49.
    McGraw AP, Bagley J, Chen W, Galayda C, Nickerson H, Armani A, Caprio M, Carmeliet P, Jaffe IZ (2013) Aldosterone increases early atherosclerosis and promotes plaque inflammation through a placental growth factor-dependent mechanism. J Am Heart Assoc 2:e000018PubMedGoogle Scholar
  50. 50.
    Mendelsohn ME (2005) In hypertension, the kidney is not always the heart of the matter. J Clin Invest 115(4):840–844PubMedGoogle Scholar
  51. 51.
    Michea L, Delpiano AM, Hitschfeld C, Lobos L, Lavandero S, Marusic ET (2005) Eplerenone blocks nongenomic effects of aldosterone on the Na+/H + exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels. Endocrinology 146(3):973–980PubMedCrossRefGoogle Scholar
  52. 52.
    Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ (2005) Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45(8):1243–1248PubMedCrossRefGoogle Scholar
  53. 53.
    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(5):434–442PubMedCrossRefGoogle Scholar
  54. 54.
    Miyata K, Rahman M, Shokoji T, Nagai Y, Zhang GX, Sun GP, Kimura S, Yukimura T, Kiyomoto H, Kohno M et al (2005) Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells. J Am Soc Nephrol 16(10):2906–2912PubMedCrossRefGoogle Scholar
  55. 55.
    Montezano AC, Callera GE, Yogi A, He Y, Tostes RC, He G, Schiffrin EL, Touyz RM (2008) Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways. Arterioscler Thromb Vasc Biol 28(8):1511–1518PubMedCrossRefGoogle Scholar
  56. 56.
    Nagai Y, Metter EJ, Earley CJ, Kemper MK, Becker LC, Lakatta EG, Fleg JL (1998) Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation 98(15):1504–1509PubMedCrossRefGoogle Scholar
  57. 57.
    Nagase M, Shibata S, Yoshida S, Nagase T, Gotoda T, Fujita T (2006) Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker. Hypertension 47(6):1084–1093PubMedCrossRefGoogle Scholar
  58. 58.
    Nagata K, Obata K, Xu J, Ichihara S, Noda A, Kimata H, Kato T, Izawa H, Murohara T, Yokota M (2006) Mineralocorticoid receptor antagonism attenuates cardiac hypertrophy and failure in low-aldosterone hypertensive rats. Hypertension 47(4):656–664PubMedCrossRefGoogle Scholar
  59. 59.
    Nariai T, Fujita K, Mori M, Katayama S, Hori S, Matsui K (2012) Antihypertensive and cardiorenal protective effects of SM-368229, a novel mineralocorticoid receptor antagonist, in aldosterone/salt-treated rats. Pharmacology 89(1–2):44–52PubMedCrossRefGoogle Scholar
  60. 60.
    Nariai T, Fujita K, Mori M, Katayama S, Hori S, Matsui K (2012) SM-368229, a novel promising mineralocorticoid receptor antagonist, shows antihypertensive efficacy with minimal effect on serum potassium level in rats. J Cardiovasc Pharmacol 59(5):458–464PubMedCrossRefGoogle Scholar
  61. 61.
    Newfell BG, Iyer LK, Mohammad NN, McGraw AP, Ehsan A, Rosano G, Huang PL, Mendelsohn ME, Jaffe IZ (2011) Aldosterone regulates vascular gene transcription via oxidative stress-dependent and -independent pathways. Arterioscler Thromb Vasc Biol 31(8):1871–1880PubMedCrossRefGoogle Scholar
  62. 62.
    O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr (1999) Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340(1):14–22PubMedCrossRefGoogle Scholar
  63. 63.
    Orlandi A, Bennett M (2010) Progenitor cell-derived smooth muscle cells in vascular disease. Biochem Pharmacol 79(12):1706–1713PubMedCrossRefGoogle Scholar
  64. 64.
    Orr AW, Hastings NE, Blackman BR, Wamhoff BR (2010) Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis. J Vasc Res 47(2):168–180PubMedCrossRefGoogle Scholar
  65. 65.
    Pitt B, Williams G, Remme W, Martinez F, Lopez-Sendon J, Zannad F, Neaton J, Roniker B, Hurley S, Burns D et al (2001) The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 15(1):79–87PubMedCrossRefGoogle Scholar
  66. 66.
    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(10):709–717PubMedCrossRefGoogle Scholar
  67. 67.
    Pu Q, Neves MF, Virdis A, Touyz RM, Schiffrin EL (2003) Endothelin antagonism on aldosterone-induced oxidative stress and vascular remodeling. Hypertension 42(1):49–55PubMedCrossRefGoogle Scholar
  68. 68.
    Rajagopalan S, Duquaine D, King S, Pitt B, Patel P (2002) Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation 105(18):2212–2216PubMedCrossRefGoogle Scholar
  69. 69.
    Rautureau Y, Paradis P, Schiffrin EL (2011) Cross-talk between aldosterone and angiotensin signaling in vascular smooth muscle cells. Steroids 76(9):834–839PubMedGoogle Scholar
  70. 70.
    Raz-Pasteur A, Gamliel-Lazarovich A, Coleman R, Keidar S (2012) Eplerenone reduced lesion size in early but not advanced atherosclerosis in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol 60(6):508–512PubMedCrossRefGoogle Scholar
  71. 71.
    Rita OD, Hackam DG, Spence JD (2012) Effects of aldosterone on human atherosclerosis: plasma aldosterone and progression of carotid plaque. Can J Cardiol 28:706–711PubMedCrossRefGoogle Scholar
  72. 72.
    Rizzoni D, Porteri E, Castellano M, Bettoni G, Muiesan ML, Muiesan P, Giulini SM, Agabiti-Rosei E (1996) Vascular hypertrophy and remodeling in secondary hypertension. Hypertension 28(5):785–790PubMedCrossRefGoogle Scholar
  73. 73.
    Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E et al (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19(1):31–44PubMedCrossRefGoogle Scholar
  74. 74.
    Roncal C, Buysschaert I, Gerdes N, Georgiadou M, Ovchinnikova O, Fischer C, Stassen JM, Moons L, Collen D, De Bock K et al (2010) Short-term delivery of anti-PlGF antibody delays progression of atherosclerotic plaques to vulnerable lesions. Cardiovasc Res 86(1):29–36PubMedCrossRefGoogle Scholar
  75. 75.
    Ronzaud C, Loffing J, Bleich M, Gretz N, Grone HJ, Schutz G, Berger S (2007) Impairment of sodium balance in mice deficient in renal principal cell mineralocorticoid receptor. J Am Soc Nephrol 18(6):1679–1687PubMedCrossRefGoogle Scholar
  76. 76.
    Ronzaud C, Loffing J, Gretz N, Schutz G, Berger S (2011) Inducible renal principal cell-specific mineralocorticoid receptor gene inactivation in mice. Am J Physiol Renal Physiol 300(3):F756–F760PubMedCrossRefGoogle Scholar
  77. 77.
    Sanz-Rosa D, Cediel E, de las Heras N, Miana M, Balfagon G, Lahera V, Cachofeiro V (2005) Participation of aldosterone in the vascular inflammatory response of spontaneously hypertensive rats: role of the NFkappaB/IkappaB system. J Hypertens 23(6):1167–1172PubMedCrossRefGoogle Scholar
  78. 78.
    Sanz-Rosa D, Oubina MP, Cediel E, De las Heras N, Aragoncillo P, Balfagon G, Cachofeiro V, Lahera V (2005) Eplerenone reduces oxidative stress and enhances eNOS in SHR: vascular functional and structural consequences. Antioxid Redox Signal 7(9–10):1294–1301PubMedCrossRefGoogle Scholar
  79. 79.
    Somlyo AP, Somlyo AV (1994) Signal transduction and regulation in smooth muscle. Nature 372(6503):231–236PubMedCrossRefGoogle Scholar
  80. 80.
    Steppan J, Barodka V, Berkowitz DE, Nyhan D (2011) Vascular stiffness and increased pulse pressure in the aging cardiovascular system. Cardiol Res Pract 2011:263585PubMedGoogle Scholar
  81. 81.
    Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, Seidlerova J, Richart T, Jin Y, Olszanecka A, Malyutina S, Casiglia E et al (2011) Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA 305(17):1777–1785PubMedCrossRefGoogle Scholar
  82. 82.
    Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S (2011) Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis of randomized controlled trials (Cochrane review). Am J Hypertens 24(8):843–853PubMedCrossRefGoogle Scholar
  83. 83.
    Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010) Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci 65(10):1028–1041PubMedCrossRefGoogle Scholar
  84. 84.
    Van Belle E, Bauters C, Wernert N, Hamon M, McFadden EP, Racadot A, Dupuis B, Lablanche JM, Bertrand ME (1995) Neointimal thickening after balloon denudation is enhanced by aldosterone and inhibited by spironolactone, and aldosterone antagonist. Cardiovasc Res 29(1):27–32PubMedCrossRefGoogle Scholar
  85. 85.
    Vinson GP, Coghlan JP (2010) Expanding view of aldosterone action, with an emphasis on rapid action. Clin Exp Pharmacol Physiol 37(4):410–416PubMedCrossRefGoogle Scholar
  86. 86.
    Virdis A, Neves MF, Amiri F, Viel E, Touyz RM, Schiffrin EL (2002) Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension 40(4):504–510PubMedCrossRefGoogle Scholar
  87. 87.
    Vukusich A, Kunstmann S, Varela C, Gainza D, Bravo S, Sepulveda D, Cavada G, Michea L, Marusic ET (2010) A randomized, double-blind, placebo-controlled trial of spironolactone on carotid intima-media thickness in nondiabetic hemodialysis patients. Clin J Am Soc Nephrol 5(8):1380–1387PubMedCrossRefGoogle Scholar
  88. 88.
    Wakabayashi K, Suzuki H, Sato T, Iso Y, Katagiri T, Takeyama Y (2006) Eplerenone suppresses neointimal formation after coronary stent implantation in swine. Int J Cardiol 107(2):260–266PubMedCrossRefGoogle Scholar
  89. 89.
    Wang M, Takagi G, Asai K, Resuello RG, Natividad FF, Vatner DE, Vatner SF, Lakatta EG (2003) Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension 41(6):1308–1316PubMedCrossRefGoogle Scholar
  90. 90.
    Wang M, Zhang J, Jiang LQ, Spinetti G, Pintus G, Monticone R, Kolodgie FD, Virmani R, Lakatta EG (2007) Proinflammatory profile within the grossly normal aged human aortic wall. Hypertension 50(1):219–227PubMedCrossRefGoogle Scholar
  91. 91.
    Ward MR, Kanellakis P, Ramsey D, Funder J, Bobik A (2001) Eplerenone suppresses constrictive remodeling and collagen accumulation after angioplasty in porcine coronary arteries. Circulation 104(4):467–472PubMedCrossRefGoogle Scholar
  92. 92.
    Wendler A, Albrecht C, Wehling M (2012) Nongenomic actions of aldosterone and progesterone revisited. Steroids 77(10):1002–1006PubMedCrossRefGoogle Scholar
  93. 93.
    Widimsky J Jr, Strauch B, Petrak O, Rosa J, Somloova Z, Zelinka T, Holaj R (2012) Vascular disturbances in primary aldosteronism: clinical evidence. Kidney Blood Press Res 35(6):529–533PubMedCrossRefGoogle Scholar
  94. 94.
    Wu SY, Yu YR, Cai Y, Jia LX, Wang X, Xiao CS, Tang CS, Qi YF (2012) Endogenous aldosterone is involved in vascular calcification in rat. Exp Biol Med (Maywood) 237(1):31–37CrossRefGoogle Scholar
  95. 95.
    Xiao F, Puddefoot JR, Vinson GP (2000) Aldosterone mediates angiotensin II-stimulated rat vascular smooth muscle cell proliferation. J Endocrinol 165(2):533–536PubMedCrossRefGoogle Scholar
  96. 96.
    Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, Group E-HS (2011) Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 364(1):11–21PubMedCrossRefGoogle Scholar
  97. 97.
    Zhou X, Crook MF, Sharif-Rodriguez W, Zhu Y, Ruben Z, Pan Y, Urosevic-Price O, Wang L, Flattery AM, Forrest G et al (2011) Chronic antagonism of the mineralocorticoid receptor ameliorates hypertension and end organ damage in a rodent model of salt-sensitive hypertension. Clin Exp Hypertens 33(8):538–547PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Amy McCurley
    • 1
  • Adam McGraw
    • 1
  • Dafina Pruthi
    • 1
  • Iris Z. Jaffe
    • 1
    Email author
  1. 1.Molecular Cardiology Research InstituteTufts Medical CenterBostonUSA

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