TY - JOUR
T1 - Apolipoprotein (a) fragments in relation to human carotid plaque instability
AU - Fortunato, John E.
AU - Bassiouny, Hisham S.
AU - Song, Ruo H.
AU - Kocharian, Hrachia
AU - Glagov, Seymour
AU - Edelstein, Celina
AU - Scanu, Angelo M.
N1 - Funding Information:
Supported in part by National Institute of Health Grant #R01-HL55296-01. Support for Dr Fortunato: Cardiovascular Pathophysiology and Biochemistry Training Program, University of Chicago, Grant #5T32 HL07237.
PY - 2000
Y1 - 2000
N2 - Purpose: 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 metaltoproteinase 2 and matrix metaltoproteinase 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.
AB - Purpose: 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 metaltoproteinase 2 and matrix metaltoproteinase 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.
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U2 - 10.1067/mva.2000.107757
DO - 10.1067/mva.2000.107757
M3 - Article
C2 - 10957664
AN - SCOPUS:0033831397
SN - 0741-5214
VL - 32
SP - 555
EP - 563
JO - Journal of Vascular Surgery
JF - Journal of Vascular Surgery
IS - 3
ER -