Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms

Elastolytic matrix metalloproteinases (MMPs) have been implicated in the pa thogenesis of abdominal aortic aneurysms (AAA), a disorder characterized by chronic aortic wall inflammation and destruction of medial elastin. The pu rpose of this study was to determine if human macrophage elastase (HME; MMP -12) might participate in this disease. By reverse transcription-polymerase chain reaction, HME mRNA was consistently demonstrated in AAA and atherosc lerotic occlusive disease (AOD) tissues(six of six), but in only one of six normal aortas. Immunoreactive proteins corresponding to proHME and two pro ducts of extracellular processing were present in seven of seven AAA tissue extracts. Total HME recovered from AAA tissue was sevenfold greater than n ormal aorta (P < 0.001), and the extracted enzyme exhibited activity in vit ro. Production of HME was demonstrated in the media of AAA tissues by in si tu hybridization and immunohistochemistry, but HME was not detected within the media of normal or AOD specimens. Importantly, immunoreactive HME was s pecifically localized to residual elastin fragments within the media of AAA tissue, particularly areas adjacent to nondilated normal aorta. In vitro, the fraction of MMP-12 sequestered by insoluble elastin was two- to fivefol d greater than other elastases found in AAA tissue. Therefore, HME is promi nently expressed by aneurysm-infiltrating macrophages within the degenerati ng aortic media of AAA, where it is also bound to residual elastic fiber fr agments. Because elastin represents a critical component of aortic wall str ucture and a matrix substrate for metalloelastases, HME may have a direct a nd singular role in the pathogenesis of aortic aneurysms.