Apolipoprotein (a) fragments in relation to human carotid plaque instability.
OBJECTIVE
An elevated plasma level of lipoprotein (a) is an independent risk factor for atherothrombotic cardiovascular disease by yet undefined mechanisms. We have previously reported that matrix metalloproteinases cleave apolipoprotein (a) into 2 main fragments, F1 and F2, the latter (the C-terminal domain) exhibiting in vitro a high-affinity binding to extracellular matrix components, including fibrin(ogen). We therefore tested the hypothesis that the lipoprotein (a) matrix metalloproteinase-derived F2 is localized in potentially or morphologically unstable human carotid plaque at regions of increased matrix metalloproteinase activity.


METHODS
Carotid plaques removed after endarterectomy (n = 18) were evaluated for structural features indicative of instability (thin fibrous cap, inflammation, and proximity of the necrotic core to the lumen); each plaque was classified as unstable (n = 10) or stable (n = 8). Western blot analysis was performed to quantitate apolipoprotein (a) and its fragments F1 and F2 in plaque extracts. Immunohistochemical staining was used to localize apolipoprotein (a) and its fragments within the atherosclerotic plaque. In situ zymography was used to determine regions of gelatinase (matrix metalloproteinase 2 and matrix metalloproteinase 9) activity.


RESULTS
Western blot analyses demonstrated a 2.5-fold higher density of F2 in unstable plaques than in stable plaques (3.07 +/- 1.9 vs 1.18 +/- 0.8; P <.05). In morphologically unstable plaques, there was preferential distribution of F2 within regions of fibrous cap inflammation and/or foam cell accumulation and within abluminal necrotic cores. In morphologically stable plaques, however, localization was predominantly found in the medial smooth muscle cells. Regions of enhanced matrix metalloproteinase 2 and matrix metalloproteinase 9 activity co-localized with the transmural distribution of F2 within the plaque.


CONCLUSIONS
These findings suggest that F2 in regions of increased matrix metalloproteinase activity is a potential mechanism for superimposed thrombotic events in morphologically unstable human carotid plaques. The relationship between plasma lipoprotein (a) levels and accumulation of F2 and the potential correlation of F2 to human plaque disruption and thrombosis warrant further study.
Fortunato
J E
JE
Department of Surgery, Section of Vascular Surgery, University of Chicago, Chicago, IL 60637, USA.
Bassiouny
H S
HS
Song
R H
RH
Kocharian
H
H
Glagov
S
S
Edelstein
C
C
Scanu
A M
AM
D000368:Aged; D001054:Apolipoproteins A / Q000097:blood*; D002339:Carotid Arteries / Q000473:pathology; D016893:Carotid Stenosis / Q000473:pathology* / Q000601:surgery; D016894:Endarterectomy, Carotid; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*
D001054:Apolipoproteins A; D010446:Peptide Fragments