Hyaluronic acid metabolism is increased in unstable plaques.
BACKGROUND
Hyaluronic acid is expressed in atherosclerotic lesions, but its exact role in atherosclerotic disease remains unknown. As degradation of hyaluronic acid by hyaluronidase into low molecular weight hyaluronic acid (LMW-HA) is associated with inflammation and Matrix Metalloproteinase (MMP)-9 activity, we hypothesized that hyaluronic acid metabolism is increased in plaques with unstable characteristics like large lipid core, high number of macrophages, MMP-9 activity, low collagen and smooth muscle cell content.


METHODS
Protein was isolated from 68 carotid artery specimens. The adjacent plaque segment was characterized for the histological parameters: lipid core, macrophage, collagen, smooth muscle cell (SMC) content and the amount of intra-plaque thrombus. Hyaluronidase activity, total hyaluronic acid and LMW-HA expression, the standard hayaluronic acid receptor CD44s and the VEGF-A binding isoform CD44v3, MMP-9 activity and the plaque instability associated growth factor Vascular Endothial Growth Factor (VEGF)-A were analysed and correlated with histological characteristics.


RESULTS
Hyaluronidase activity, LMW-HA and CD44 expression (CD44s, CD44v3) levels were increased in atheromatous plaques compared with fibrous plaques. Total hyaluronic acid did not correlate with plaque instability. MMP-9 activity correlated with CD44s, hyaluronidase and LMW-HA expression. CD44v3 correlated with the angiogenic factor VEGF-A. In vitro stimulation of macrophages with LMW-HA increased MMP-9 activity.


CONCLUSIONS
We show for the first time that increased hyaluronic acid metabolism and elevated CD44 levels are associated with plaque destabilization potentially by increased MMP-9 activity and stimulation of angiogenesis.
Bot
Pieter T
PT
Department of Cardiology, AMC Amsterdam, The Netherlands. ptgbot@gmail.com
Pasterkamp
Gerard
G
Goumans
Marie-José
MJ
Strijder
Chaylendra
C
Moll
Frans L
FL
de Vries
Jean-Paul
JP
Pals
Steven T
ST
de Kleijn
Dominique P
DP
Piek
Jan J
JJ
Hoefer
Imo E
IE
D000368:Aged; D042683:Angiopoietin-1 / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042683:Angiopoietin-1; D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D020780:Matrix Metalloproteinase 9