Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves.
BACKGROUND
The mechanisms of extracellular matrix changes accompanying myxomatous valvular degeneration are uncertain.


RESULTS
To test the hypothesis that valvular interstitial cells mediate extracellular matrix degradation in myxomatous degeneration by excessive secretion of catabolic enzymes, we examined the functional characteristics of valvular interstitial cells in 14 mitral valves removed for myxomatous degeneration from patients with mitral regurgitation and in 11 normal mitral valves obtained at autopsy. Immunohistochemical staining assessed (1) cell phenotype using antibodies to alpha-actin (microfilaments), vimentin and desmin (intermediate filaments), smooth muscle myosin (SM1), and SMemb (a nonmuscle myosin produced by activated mesenchymal cells) and (2) the expression of proteolytic activity using antibodies to collagenases (matrix metalloproteinase [MMP]-1, MMP-13), gelatinases (MMP-2, MMP-9), cysteine endoproteases (cathepsin S and K), and interleukin-1beta, a cytokine that can induce secretion of proteolytic enzymes. Although interstitial cells in normal valves stained positively for vimentin, but not alpha-actin or desmin, cells in myxomatous valves contained both vimentin and alpha-actin or desmin (characteristics of myofibroblasts). Moreover, cells in myxomatous valves strongly expressed SMemb, MMPs, cathepsins, and interleukin-1beta, which were weakly stained in controls. Nevertheless, interstitial cells in both groups strongly expressed procollagen-I mRNA (in situ hybridization), suggesting preserved ability to synthesize collagen in myxomatous valves.


CONCLUSIONS
Interstitial cells in myxomatous valves have features of activated myofibroblasts and express excessive levels of catabolic enzymes, without altered levels of interstitial collagen mRNA. We conclude that valvular interstitial cells regulate matrix degradation and remodeling in myxomatous mitral valve degeneration.
Rabkin
E
E
Department of Pathology, Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Aikawa
M
M
Stone
J R
JR
Fukumoto
Y
Y
Libby
P
P
Schoen
F J
FJ
D000328:Adult; D000368:Aged; D002403:Cathepsins / Q000378:metabolism; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000502:physiology*; D006338:Heart Neoplasms / Q000150:complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D008943:Mitral Valve / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D008944:Mitral Valve Insufficiency / Q000209:etiology*; D008955:Models, Cardiovascular; D009232:Myxoma / Q000150:complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis
D024042:Collagen Type I; D012333:RNA, Messenger; D002403:Cathepsins; D020782:Matrix Metalloproteinases