Identification and Characterization of Novel Lysine-independent Apolipoprotein(a)-binding Sites in Fibrin(ogen) αC-domains

Abstract

Accumulation of lipoprotein(a) (Lp(a)) in atherosclerotic plaques is mediated through interaction of fibrin-(ogen) deposits with the apolipoprotein(a) (apo(a)) moiety of Lp(a). It was suggested that because apo(a) competes with plasminogen for binding to fibrin, causing inhibition of fibrinolysis, it could also promote atherothrombosis. Because the fibrin(ogen) ␣C-domains bind plasminogen and tissue-type plasminogen activator with high affinity in a Lys-dependent manner, we hypothesized that they could also bind apo(a). To test this hypothesis, we studied the interaction between the recombinant apo(a) A10 isoform and the recombinant ␣C-fragment (A␣-(221-610)) corresponding to the ␣C-do- Elevated plasma levels of lipoprotein(a) (Lp(a)) 1 and fibrinogen are independent risk factors for atherosclerotic cardiovascular diseases (1-3). Numerous in vivo experiments with transgenic animals directly proved involvement of Lp(a) and fibrinogen in the development and progression of atherosclerosis. It was demonstrated that transgenic mice expressing human apolipoprotein(a) (apo(a)), a protein component of Lp(a), are more susceptible to diet-induced atherosclerosis (4 -6). It was also shown that in apo(a)-transgenic rabbits, in which apo(a) is efficiently assembled into Lp(a), the latter substantially increases the development of aortic and coronary atherosclerosis and accelerates formation of advanced atherosclerotic lesions (7-9). Finally, it was found that fibrinogen deficiency in apo(a) transgenic mice reduces accumulation of apo(a) in the vessel walls and lesion development, suggesting that fibrin(ogen) may provide one of the major sites to which apo(a) binds to the vessel wall and participates in the generation of atherosclerosis (10).Although the mechanism through which Lp(a) and fibrin-(ogen) may contribute to the atherogenic processes is still not clearly understood, it seems to be connected with their structure and their ability to interact with each other. Lp(a) is a lipoprotein particle composed of a lipid core and two disulfidelinked apolipoproteins, apoB-100 and apo(a). The lipid core and apoB-100 are shared with low density lipoprotein, the major transporter of cholesterol in human plasma; at the same time, apo(a), which shows a high degree of homology to plasminogen, confers unique properties on Lp(a) (11,12). Because of these structural similarities, Lp(a) was implicated in the delivery of cholesterol to injured blood vessels (13) and in competition with plasminogen for binding to fibrin and cellular surfaces (14); interaction between Lp(a) and fibrin may play a critical role in both cases. It has been established that both plasminogen and apo(a) contain Lys-binding sites (15,16). It is also known that binding of plasminogen to fibrin via these sites is important for its conversion into an active enzyme, plasmin (17)(18)(19). Numerous studies have demonstrated that Lp(a) and apo(a) also interact with fibrin(ogen) via their Lys-binding sites and compete effectively with plasminogen for its interaction with fi...

Altered fibrin clot properties in patients on long-term haemodialysis: relation to cardiovascular mortality

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Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

“…This has been interpreted to suggest a causal role for Lp(a) in altering clot structure in coronary artery disease (CAD) patients compared with healthy controls, thereby contributing to CAD risk. This may reflect the ability of the apo(a) component of Lp(a) to bind with high affinity to the fibrin(ogen) C region (88). This interaction may disrupt the lateral association of fibrin protofibrils, thereby resulting in the formation of thinner fibrin fibers (Fig.…”

Fibrin Clot Structure and Function

“…The fibrin(ogen) ␣C-regions contain apolipoprotein(a)-binding sites. 78 Additional studies are required to investigate how these binding sites may play a role in fibrin structure and fibrinolysis.…”