Matrix Metalloproteinase-9 Expression in Calcified Human Aortic Valves: A Histopathologic, Immunohistochemical, and Ultrastructural Study.
The hallmarks of calcific aortic valve disease (CAVD) are the significant quantitative and qualitative changes that occur in the extracellular matrix (ECM), which ultimately lead to increased leaflet stiffness and obstruction of left ventricular outflow. Mounting evidence suggests that ECM remodeling not only contribute to valve cell dysfunction but also alter certain cell signaling pathways responsible for the initiation and progression of the disease state. Matrix metalloproteinases (MMPs), collectively called matrixins, are a family of enzymes known to participate in numerous ECM remodeling events during embryonic development and in disease. The aim of the present study was to evaluate whether changes in MMP-9 expression might be involved in the pathophysiology of CAVD. For this purpose, we have analyzed a total of 19 pathologic valves from patients who underwent aortic valve replacement for calcific aortic stenosis. Microscopically, the cusp tissue showed diffuse fibrosis, neovascularization, and abnormal ECM remodeling with collagen disorganization and mineralization. Western blot and immunohistochemical analyses have been performed on both the areas overlying and remote from the mineral deposits. Protein expression data evidenced a significant upregulation of MMP-9 in the calcified lesion area. Consistent with these observations, immunohistochemistry demonstrated that MMP-9 protein was almost exclusively localized near or around the mineralized nodules, whereas was generally quite weak or absent in areas devoid of any calcification. Our data suggest that MMP-9 may play a key role in CAVD probably by promoting the fibrotic and procalcific remodeling of the ECM.
*Department of Biology, Ecology and Earth Sciences (Di.B.E.S.T.), University of Calabria, Arcavacata di Rende, Cosenza †Department of Cardiothoracic Surgery and Cardiology, Sant'Anna Hospital, Catanzaro, Italy ‡Department of Pharmacy and Sciences of Health and Nutrition, University of Calabria, Arcavacata di Rende, Cosenza.
Ida
I
Perrotta
Alfonso
A
Sciangula
Saveria
S
Aquila
Sergio
S
Mazzulla
D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D001024:Aortic Valve Stenosis / Q000175:diagnosis*; D002114:Calcinosis / Q000175:diagnosis*; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis*; D020257:Ventricular Remodeling
D020780:Matrix Metalloproteinase 9