Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses

Yuki Izawa-Ishizawa, Masaki Imanishi, Yoshito Zamami, Hiroki Toya, Tomoko Nagao, Marin Morishita, Koichi Tsuneyama, Yuya Horinouchi, Yoshitaka Kihira, Kenshi Takechi, Yasumasa Ikeda, Koichiro Tsuchiya, Masanori Yoshizumi, Toshiaki Tamaki, Keisuke Ishizawa

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Objective:Aortic dissection is a life-threatening disease. At present, the only therapeutic strategies available are surgery and antihypertensive drugs. Moreover, the molecular mechanisms underlying the onset of aortic dissection are still unclear. We established a novel aortic dissection model in mice using pharmacologically induced endothelial dysfunction. We then used the Japanese Adverse Drug Event Report database to investigate the role of pitavastatin in preventing the onset of aortic dissection.Methods and results:To induce endothelial dysfunction, Nω-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, was administered to C57BL/6 mice. Three weeks later, angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, were administered with osmotic mini-pumps. False lumen formation was used as the pathological determinant of aortic dissection. The incidences of aortic dissection and death from aneurysmal rupture were significantly higher in the Nω-nitro-l-arginine methyl ester, Ang II, and BAPN (LAB) group than they were in the Ang II and BAPN (AB) group.Pitavastatin was administered orally to LAB mice. It significantly lowered the incidences of dissection and rupture. It also decreased inflammation and medial degradation, both of which were exacerbated in the LAB group. The Japanese Adverse Drug Event Report database analysis indicated that there were 113 cases of aortic dissection out of 95090 patients (0.12%) not receiving statins but only six cases out of 16668 patients receiving statins (0.04%) (odds ratio: 0.30; P=0.0043).Conclusion:Our results suggest that endothelial dysfunction is associated with the onset of aortic dissection and pitavastatin can help prevent this condition.

Original languageEnglish
Pages (from-to)73-83
Number of pages11
JournalJournal of Hypertension
Volume37
Issue number1
DOIs
Publication statusPublished - Jan 1 2019
Externally publishedYes

Keywords

  • angiotensin II
  • aortic dissection
  • endothelial dysfunction
  • lysyl oxidase inhibitor
  • nitric oxide synthase inhibitor
  • pitavastatin
  • the Japanese Adverse Drug Event Report Database

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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