title: Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt.
abstract: OBJECTIVE
  Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown.
  
  
  RESULTS
  We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm.
  
  
  CONCLUSIONS
  The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.
authors: Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors: Shu
authors: S
authors: Liu
authors: Zhongwen
authors: Z
authors: Xie
authors: Alan
authors: A
authors: Daugherty
authors: Lisa A
authors: LA
authors: Cassis
authors: Kevin J
authors: KJ
authors: Pearson
authors: Ming C
authors: MC
authors: Gong
authors: Zhenheng
authors: Z
authors: Guo
mesh_terms: D000450:Aldosterone / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001019:Aortic Rupture / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D001794:Blood Pressure; D003900:Desoxycorticosterone; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D004656:Enalapril / Q000008:administration & dosage; D000077545:Eplerenone; D019808:Losartan / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000378:metabolism*; D017673:Sodium Chloride, Dietary; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D013148:Spironolactone; D003900:Desoxycorticosterone; D000450:Aldosterone; D000077545:Eplerenone; D004656:Enalapril; D004549:Elastin; D019808:Losartan
keywords: aldosterone; aneurysm; desoxycorticosterone; receptors; salt
references: Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2605-13
references: 16973970
references: BMC Genomics. 2009 Jul 06;10:298
references: 19580648
references: N Engl J Med. 2003 Apr 3;348(14):1309-21
references: 12668699
references: J Am Coll Cardiol. 2010 Apr 6;55(14):e27-e129
references: 20359588
references: N Engl J Med. 1999 Sep 2;341(10):709-17
references: 10471456
references: J Am Coll Cardiol. 2002 Nov 6;40(9):1596-601
references: 12427411
references: J Surg Res. 2009 Aug;155(2):181-2
references: 19520386
references: Nat Med. 2012 Sep;18(9):1429-33
references: 22922412
references: BMC Genomics. 2007 Jul 16;8:237
references: 17634102
references: Annu Rev Nutr. 2004;24:401-31
references: 15189126
references: Am J Pathol. 2007 Sep;171(3):809-19
references: 17724138
references: Circ Res. 2011 Mar 4;108(5):574-81
references: 21252156
references: J Clin Invest. 2000 Jun;105(11):1605-12
references: 10841519
references: Cardiol Rev. 2004 Jan-Feb;12(1):44-8
references: 14667264
references: Am J Physiol Heart Circ Physiol. 2009 May;296(5):H1660-5
references: 19252100
references: Hypertension. 2008 Feb;51(2):218-24
references: 18158357
references: Circ Res. 2012 May 25;110(11):e73-85
references: 22539767
references: Cardiology. 2007;108(1):48-50
references: 16988504
references: Nature. 2011 May 19;473(7347):308-16
references: 21593863
references: Br J Pharmacol. 2001 Oct;134(4):865-70
references: 11606327
references: Vascular. 2009 May-Jun;17 Suppl 1:S21-9
references: 19426606
references: Circulation. 2006 Aug 1;114(5):404-413
references: 16864727
references: Br J Pharmacol. 2005 Feb;144(3):443-8
references: 15655500
references: Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):461-9
references: 17218601
references: J Pharmacol Toxicol Methods. 1992 May;27(3):161-70
references: 1498343
references: Arterioscler Thromb Vasc Biol. 2002 Apr 1;22(4):560-5
references: 11950691
references: Nat Med. 2011 Nov 13;17(12):1610-8
references: 22081025
references: Hypertension. 2010 Jun;55(6):1476-83
references: 20421514
references: Lab Invest. 1998 Sep;78(9):1059-66
references: 9759650
references: Mol Cell Endocrinol. 2012 Mar 24;350(2):248-55
references: 21930186
references: N Engl J Med. 2001 Dec 6;345(23):1689-97
references: 11759649
references: J Vasc Surg. 2010 Jul;52(1):55-61.e2
references: 20620765
references: Circulation. 2010 Feb 23;121(7):934-9
references: 20177008
references: Biochim Biophys Acta. 2010 Dec;1802(12):1188-92
references: 20713154