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.

APPROACH AND 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: Shu Liu, Zhongwen Xie, Alan Daugherty, Lisa A Cassis, Kevin J Pearson, Ming C Gong, Zhenheng Guo
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 33 Issue 7 Pg. 1568-79 (Jul 2013) ISSN: 1524-4636 [Electronic] United States
• PMID: 23661677 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Angiotensin-Converting Enzyme Inhibitors
• Mineralocorticoid Receptor Antagonists
• Receptors, Mineralocorticoid
• Sodium Chloride, Dietary
• Spironolactone
• Desoxycorticosterone
• Aldosterone
• Eplerenone
• Enalapril
• Elastin
• Losartan

Topics

• Aldosterone (blood)
• Angiotensin II Type 1 Receptor Blockers (administration & dosage)
• Angiotensin-Converting Enzyme Inhibitors (administration & dosage)
• Animals
• Aorta (drug effects, metabolism, pathology)
• Aortic Aneurysm, Abdominal (chemically induced, drug therapy, etiology, metabolism, pathology, physiopathology)
• Aortic Aneurysm, Thoracic (chemically induced, drug therapy, etiology, metabolism, pathology, physiopathology)
• Aortic Rupture (chemically induced, drug therapy, etiology, metabolism, pathology, physiopathology)
• Apoptosis
• Blood Pressure
• Desoxycorticosterone
• Disease Models, Animal
• Elastin (metabolism)
• Enalapril (administration & dosage)
• Eplerenone
• Losartan (administration & dosage)
• Male
• Mice
• Mice, Inbred C57BL
• Mineralocorticoid Receptor Antagonists (administration & dosage)
• Muscle, Smooth, Vascular (metabolism, pathology)
• Oxidative Stress
• Receptors, Mineralocorticoid (agonists, metabolism)
• Sodium Chloride, Dietary
• Spironolactone (administration & dosage, analogs & derivatives)
• Time Factors