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

Robert W. Thompson, Dennis R. Holmes, Renato A. Mertens, Shixiong Liao, Mitchell D. Botney, Robert P. Mecham, Howard G. Welgus, William C. Parks

Research output: Contribution to journalArticlepeer-review

402 Scopus citations

Abstract

Abdominal aortic aneurysms (AAA) are characterized by disruption and degradation of the elastic media, yet the elastolytic proteinases involved and their cellular sources are undefined. We examined if 92-kD gelatinase, an elastolytic matrix metalloproteinase, participates in the pathobiology of AAA. Gelatin zymography of conditioned medium from normal, atheroocclusive disease (AOD), or AAA tissues in organ culture showed that all tissues produced 72-kD gelatinase. AOD and AAA cultures also secreted 92-kD gelatinase, but significantly more enzyme was released from AAA tissues. ELISA confirmed that AAA tissues released ∼ 2-fold more 92-kD gelatinase than AOD tissue and ∼ 10-fold more than normal aorta. Phorbol ester induced a 5.3-fold increase in 92-kD gelatinase secretion by normal aorta and AOD and an 11.5-fold increase by AAA. By immunohistochemistry, 92-kD gelatinase was not detected in normal aorta and was only occasionally seen within the neointimal lesions of AOD tissue. In all AAA specimens, however, 92-kD gelatinase was readily localized to numerous macrophages in the media and at the adventitial-medial junction. The expression of 92-kD gelatinase mRNA by aneurysminflltrating macrophages was confirmed by in situ hybridization. These results demonstrate that diseased aortic tissues secrete greater amounts of gelatinolytic activity than normal aorta primarily due to increased production of 92-kD gelatinase. In addition, the localization of 92-kD gelatinase to macrophages in the damaged wall of aneurysmal aortas suggests that chronic release of this elastolytic metalloproteinase contributes to extracellular matrix degradation in AAA.

Original languageEnglish
Pages (from-to)318-326
Number of pages9
JournalJournal of Clinical Investigation
Volume96
Issue number1
DOIs
StatePublished - Jul 1995

Keywords

  • 92-kilodalton gelatinase
  • Aortic aneurysm
  • Elastin
  • Macrophages
  • Metalioproteinases

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