Metalloproteinases in degenerative aortic disease

Abstract

1. Atherosclerosis and aneurysm of the abdominal aorta are associated with thinning of the medial connective tissue. We have investigated the presence of the connective-tissue-degrading metalloproteinases in homogenates prepared from atherosclerotic, aneurysmal and control aortic media. 2. Gelatinase activity was much increased in homogenates from atherosclerotic and aneurysmal aorta [10.9 +/- 1.8 and 13.3 +/- 3.3 micrograms of gelatin hydrolysed h-1 (mg of protein)-1 respectively]. This gelatinase activity was highest at the luminal aspect of the aortic media, where the activity increased three- to five-fold after the destruction of alpha 2-macroglobulin. Zymograms demonstrated the principal gelatinase in atherosclerotic aorta to have a molecular mass of about 92 kDa, whereas in aneurysmal aorta there was a spectrum of gelatinase activity from 92 to 55 kDa. 3. Collagenase and stromelysin (proteoglycanase) could be detected by immunoblotting in homogenates of aneurysmal aorta, but rarely in atherosclerotic aorta and never in control aorta. Collagenase and stromelysin activities were low, but increased two- to three-fold after the destruction of tissue inhibitor of metalloproteinases. Collagenase and stromelysin activities were highest at the adventitial aspect of aneurysmal media. 4. The secretion of gelatinase by inflammatory cells at the intima of diseased aorta could have a pathological role in establishing atherosclerotic plaques and medial thinning. Secretion of collagenase, gelatinase and stromelysin from the adventitia could accelerate connective tissue degradation in the media of aneurysmal aorta.

Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages.

“…Indeed, using zymography or substrate-degradation assays, various investigators have found elastolytic metalloenzymes in extracts of AAA (19)(20)(21)(22)(23), and, in agreement with our findings, these earlier studies found prominent activity at -80-92 kD (20,21). We have shown that 92-kD gelatinase is actively secreted by aortic tissues using substrate zymography and a highly specific ELISA, and that the production of this elastolytic metalloproteinase is markedly increased in cultures of AAA compared to normal and atheroocclusive disease tissues.…”

“…However, clinical and pathologic differences between patients with aneurysms and those with occlusive atherosclerosis have challenged these assumptions (1-3, 43, 44), and investigations of the pathobiology of AAA have begun to assess the role of aneurysm-related connective tissue degrading enzymes in this disease (7,(15)(16)(17)(18)(19)(20)(21)(22)(23). Because aneurysmal change is characterized by a marked decrease in aortic elastin, much of this effort has focused on known elastin degrading enzymes, such as the serine protease human neutrophil elastase.…”

“…Because elastin is normally a highly stable extracellular matrix protein ( 13,14), locally active elastolytic proteinases likely contribute to aneurysmal dilatation by progressive degradation of this structurally important aortic wall component ( 15,16). In this context, increased proteolytic activities have been described in AAA, including serine elastases ( 17), plasminogen activators (18), and matrix metalloproteinases (MMPs) (19)(20)(21)(22), some or all of which may be involved in aortic wall elastin degradation (23).…”

“…Indeed, a metallogelatinase of 80-92 kD has been described in extracts of aneurysm tissue (19)(20)(21)(22)(23). Although 92-kD gelatinase is considered to be a relatively weak elastase as compared to serine enzymes, such as human neutrophil elastase (35,36), sustained local production may result in pronounced and progressive degradation of elastin in the aortic media.…”

Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas

“…The ability of certain MMPs, e.g., MMP-2, -3, -9, and -12, to degrade elastin may have particular relevance to AAA formation, as human AAAs exhibit abundant MMP-2 and MMP -9 expression (21,22) and, in some cases, excessive MMP-1 and MMP-3 (4-6). In experimental models, targeted disruption of MMP-9 results in decreased elastin fiber degradation after elastase perfusion in mouse aortas and suppresses the subsequent development of aortic aneurysms (23).…”