Elsevier

Cardiovascular Pathology

Volume 9, Issue 5, September–October 2000, Pages 281-286
Cardiovascular Pathology

Articles
Matrix Metalloproteinase Expression in Nonrheumatic Aortic Stenosis

https://doi.org/10.1016/S1054-8807(00)00043-0Get rights and content

Abstract

Background: Nonrheumatic aortic stenosis (NAS) is considered to be a degenerative process characterized by valve thickening, fibrocalcific masses, collagen disarray, and an inflammatory infiltrate. The matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent enzymes produced by inflammatory cells that are capable of degrading collagen, elastin, and proteoglycans. This study sought to test the hypothesis that MMPs are involved in the pathogenesis of NAS. Methods and Results: Aortic values were obtained from nine patients with NAS undergoing valve replacement and from four patients without NAS during autopsy. Microscopic analysis of NAS specimens revealed variable areas of calcium deposits, fibrosis, and an extensive cellular infiltrate consisting of macrophages, lymphocytes, and fibroblasts. Control aortic valves demonstrated normal architecture, a predominance of fibroblasts, occasional scattered macrophages, and no lymphocytes. Immunohistochemical staining with antibodies to MMP-1, -2, -3 and -9 revealed expression of each enzyme in macrophages, lymphocytes, and fibroblasts of all NAS patients. MMP-1, -2 and -3 were expressed by resident fibroblasts and macrophages in normal valves, but to a lesser degree. MMP-9 was not identified in normal valves. Conclusions: The current study confirms an inflammatory infiltrate composed of macrophages and lymphocytes in NAS. Additionally, the increased expression of MMP-1, -2, and -3, along with the unique expression of MMP-9 in NAS valve leaflets was documented. These findings are consistent with the hypothesis that NAS is associated with chronic inflammation and that the increased expression of MMPs may contribute to the pathogenesis of this disease process.

Section snippets

Tissue Acquisition and Preparation

Aortic valves were obtained at the time of surgery in nine male patients with aortic stenosis undergoing valve replacement at the Veterans Administration Medical Center, La Jolla, California. Additionally, aortic leaflets were obtained at the time of autopsy from four patients who died of noncardiac disease without aortic stenosis for comparison.

Preparation of the valve leaflets was as follows: sections for analysis were taken from a vertically orientated cut through the aortic cusps and sinus

Leaflet Architecture

Histologic analysis of the NAS valves demonstrated striking differences when compared with the aortic valves obtained from the control subjects, as seen in Table 1. All valves from patients with NAS demonstrated marked leaflet fibrosis and calcium deposition. The aortic valve leaflets obtained from the patients without a history of NAS exhibited neither of these characteristics. A hypercellular inflammatory infiltrate was present in 77% of the NAS specimens. None of the valve tissue from

Discussion

This study has demonstrated enhanced expression of MMP-1 (interstitial collagenase), MMP-2 (Gelatinase A), and MMP-3 (stromelysin) in aortic valves of patients with severe aortic stenosis. In addition, MMP-9 (gelatinase B) expression was documented exclusively in the valve leaflets of patients with aortic stenosis. Together, these metalloenzymes have the capability of degrading the collagenous and elastin components of the aortic valve. Importantly, activated MMP-3 can also activate MMP-1 and

Conclusion

In conclusion, the findings reported in this study confirm the presence of an inflammatory infiltrate composed of macrophages and lymphocytes in association with NAS. Additionally, using immunohistochemical techniques, the presence of increased expression of MMP-1, -2, and -3 and the unique expression of MMP-9 in NAS valve leaflets was documented. These findings are consistent with the hypothesis that NAS is an active process associated with chronic inflammation. The presence of MMPs within the

References (29)

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