Neutrophil-Derived Matrix Metalloproteinase 9 Triggers Acute Aortic Dissection
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 further define 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 (AngII) were significantly elevated in blood samples from the AAD patients than in those from the patients with non-ruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing AngII to immature mice that had been received a lysyl oxidase inhibitor, β-aminopropionitrile monofumarate (BAPN). AAD was successfully developed in the thoracic aorta by AngII administration to BAPN-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 RT-PCR, gelatin zymography and immunohistochemistry. The incidence of AAD was significantly reduced by 40% following the administration of an MMP inhibitor and almost completely blocked in MMP9-/- mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of 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 AngII.
- Received March 8, 2012.
- Accepted October 22, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited