Neutrophil-derived matrix metalloproteinase 9 triggers acute aortic dissection

Tomohiro Kurihara, Ryoko Shimizu-Hirota, Masayuki Shimoda, Takeshi Adachi, Hideyuki Shimizu, Stephen J. Weiss, Hiroshi Itoh, Shingo Hori, Naoki Aikawa, Yasunori Okada

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

BACKGROUND-: Acute aortic dissection (AAD) is a life-threatening vascular disease without effective pharmaceutical therapy. Matrix metalloproteinases (MMPs) are implicated in the development of chronic vascular diseases including aneurysm, but the key effectors and mechanism of action remain unknown. To define further the role of MMPs in AAD, we screened circulating MMPs in AAD patients, and then generated a novel mouse model for AAD to characterize the mechanism of action. METHODS AND RESULTS-: MMP9 and angiotensin II were elevated significantly in blood samples from AAD patients than in those from the patients with nonruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, β-aminopropionitrile monofumarate. AAD was developed successfully in the thoracic aorta by angiotensin II administration to β-aminopropionitrile monofumarate-treated wild-type mice, with an incidence of 20%, 80%, and 100% after 6, 12, and 24 hours, respectively. Neutrophil infiltrations were observed in the intima of the thoracic aorta, and the overexpression of MMP9 in the aorta was demonstrated by reverse transcription polymerase chain reaction, gelatin zymography, and immunohistochemistry. The incidence of AAD was reduced significantly by 40% following the administration of an MMP inhibitor and was almost blocked completely in MMP mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of anti-granulocyte- differentiation antigen-1 (anti-Gr-1) antibody also significantly decreased the incidence of AAD. CONCLUSIONS-: These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II.

Original languageEnglish
Pages (from-to)3070-3080
Number of pages11
JournalCirculation
Volume126
Issue number25
DOIs
Publication statusPublished - 2012 Dec 18

Keywords

  • MMP9
  • acute aortic dissection
  • angiotensin II
  • leukocytes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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