Apo(a) promotes thrombosis in a vascular injury model by a mechanism independent of plasminogen.
OBJECTIVE
Structural similarity between apolipoprotein(a) [apo(a)], the unique apoprotein of lipoprotein(a), and plasminogen (Plg), the zymogen for plasmin, results in inhibition of functions of Plg by apo(a) in vitro. The objective of this study was to evaluate the interaction of Plg and apo(a) in vivo.


RESULTS
Vascular injury was induced in the carotid artery with a perivascular cuff in: (i) wild-type (WT); (ii) Plg deficient (Plg-/-); (iii) apo(a) (6 KIV construct) transgenic [apo(a)tg]; and (iv) apo(a) transgenic and Plg deficient [apo(a):Plg-/-] mice. At 10 days after cuff placement, the media and adventitia area were increased in the injured carotids compared with the uninjured carotids, and collagen deposition was greater in apo(a)tg, Plg-/- and apo(a):Plg-/- mice compared with WT mice. The incidence of a thrombus was greater (P < 0.05) in apo(a):Plg-/- mice (83%) than WT (20%), Plg-/- (12%), and apo(a)tg mice (9%). In the thrombi from apo(a)tg and apo(a):Plg-/- mice, P-selectin and von Willebrand factor immunostaining, indicating a platelet-rich thrombi, was greater than in WT and Plg-/- mice. The presence of fibrin(ogen) in the thrombi was greater in Plg-/- and apo(a):Plg-/- mice than apo(a)tg and WT mice. Of the four genotypes, only the apo(a):Plg-/- mice had both increased platelet and increased fibrin(ogen) deposition.


CONCLUSIONS
The major finding of this study is the high incidence of thrombosis after vascular injury in apo(a)transgenic mice in a Plg deficient background, providing strong evidence for a prothrombotic role of apo(a) independent of Plg in vivo.
Sha
J
J
Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
McCullough
B
B
Hart
E
E
Nassir
F
F
Davidson
N O
NO
Hoover-Plow
J
J
D000818:Animals; D001054:Apolipoproteins A / Q000502:physiology*; D001792:Blood Platelets / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D020212:Carotid Artery Injuries / Q000150:complications* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D005337:Fibrin / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D010958:Plasminogen / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology*
D001054:Apolipoproteins A; D005337:Fibrin; D010958:Plasminogen; D003094:Collagen