Protective effects of selective mineralocorticoid receptor antagonist against aortic aneurysm progression in a novel murine model.

Abstract

BACKGROUND:

The optimal medical management to delay the progression of aortic aneurysms has not been fully clarified, and the only standard treatment at present is antihypertensive therapy. Previous studies have shown beneficial effects of selective mineralocorticoid receptor (MR) antagonists on cardiovascular remodeling. The aim of the present study was to investigate the effect of a selective MR antagonist on aortic aneurysm progression.

METHODS:

Seven-week-old C57BL/6J male mice were administered with angiotensin II and β-aminopropionitrile for 4 weeks. The mice received either vehicle or eplerenone, a selective MR antagonist (100 mg/kg daily) every day by gavage, starting at 7 weeks of age. The production of inflammatory cytokines in cultures of high mobility group box-1-stimulated macrophages with or without a MR antagonist was also analyzed using an enzyme-linked immunosorbent assay.

RESULTS:

Although no differences were found in the peak systolic blood pressure between the experimental groups, the mice in the eplerenone group showed a significant reduction in aneurysm development. On histologic analysis, coarse and stretched elastic fibers were markedly improved in the aortic wall in the eplerenone group. Real-time polymerase chain reaction of both aortic wall and perivascular adipose tissue demonstrated the expression of tumor necrosis factor-α, interleukin-6, and matrix metalloproteinase-2 was significantly decreased in eplerenone group, and that of monocyte chemoattractant protein-1 in the aortic wall was also significantly decreased. Macrophage infiltration in the aortic wall and perivascular adipose tissue in the eplerenone group was also significantly decreased. The production of tumor necrosis factor-α and interleukin-6 in macrophage culture, which was stimulated by high mobility group box-1 and CpG oligodeoxynucleotides, was also significantly decreased in the eplerenone group.

CONCLUSIONS:

Eprelenone suppressed aortic aneurysm progression through an anti-inflammatory effect. Thus, selective MR antagonists might be effective in preventing the progression of aortic aneurysms.

• Authors: Hirotsugu Kurobe, Yoichiro Hirata, Yuki Matsuoka, Noriko Sugasawa, Mayuko Higashida, Taisuke Nakayama, Mark Webster Maxfield, Yasushi Yoshida, Michio Shimabukuro, Tetsuya Kitagawa, Masataka Sata
• Journal: The Journal of surgical research (J Surg Res) Vol. 185 Issue 1 Pg. 455-62 (Nov 2013) ISSN: 1095-8673 [Electronic] United States
• PMID: 23731681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Interleukin-6
• Mineralocorticoid Receptor Antagonists
• Tumor Necrosis Factor-alpha
• Spironolactone
• Eplerenone

Topics

• Animals
• Aortic Aneurysm (drug therapy, immunology, pathology)
• Blood Pressure
• Chemokine CCL2 (genetics)
• Disease Models, Animal
• Disease Progression
• Eplerenone
• Gene Expression (drug effects, immunology)
• Interleukin-6 (genetics)
• Macrophages (drug effects, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Spironolactone (analogs & derivatives, pharmacology)
• Tumor Necrosis Factor-alpha (genetics)
• Vasculitis (drug therapy, immunology, pathology)