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

• Published in: The Journal of surgical research 2013-11, Vol.185 (1), p.455-462
• Main Authors: Kurobe, Hirotsugu, MD, PhD, Hirata, Yoichiro, MD, PhD, Matsuoka, Yuki, BS, Sugasawa, Noriko, BS, Higashida, Mayuko, MS, Nakayama, Taisuke, MD, Maxfield, Mark Webster, MD, Yoshida, Yasushi, PhD, Shimabukuro, Michio, MD, PhD, Kitagawa, Tetsuya, MD, PhD, Sata, Masataka, MD, PhD
• Format: Article
• Language: English
• Subjects: Animals; Aortic aneurysm; Aortic Aneurysm - drug therapy; Aortic Aneurysm - immunology; Aortic Aneurysm - pathology; Blood Pressure; Chemokine CCL2 - genetics; Disease Models, Animal; Disease Progression; Gene Expression - drug effects; Gene Expression - immunology; Interleukin-6 - genetics; Macrophages - drug effects; Macrophages - immunology; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists - pharmacology; MR antagonist; Preventive medicine; Spironolactone - analogs & derivatives; Spironolactone - pharmacology; Surgery; Tumor Necrosis Factor-alpha - genetics; Vasculitis - drug therapy; Vasculitis - immunology; Vasculitis - pathology
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2013.05.002

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.