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Does lipoprotein(a) (Lp(a)) complete with plasminogen in human atherosclerotic lesions and thrombi?
Insights
Lipoprotein(a) [Lp(a)] does not appear to displace plasminogen in vivo, contrary to previous hypotheses. Lp(a) preferentially binds to fibrin, potentially increasing lipid accumulation and contributing to atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Lipid Metabolism
- Thrombosis Research
Background:
- Thrombotic occlusion, a primary cause of myocardial infarction (MI), is linked to fibrin accumulation in atherosclerotic lesions.
- Lipoprotein(a) [Lp(a)], characterized by an apoprotein homologous to plasminogen, has been hypothesized to increase MI risk by interfering with fibrinolysis.
Purpose of the Study:
- To investigate the in vivo relationship between Lp(a) and plasminogen levels in normal and atherosclerotic tissues.
- To determine if Lp(a) displaces plasminogen from fibrin in atherosclerotic lesions and thrombi.
Main Methods:
- Comparison of Lp(a) and plasminogen levels in aortic intima and intravascular thrombi.
- Extraction of tissue components and elution of lysine-bound factors using epsilon-aminocaproic acid (epsilon-aca).
- Analysis of Lp(a) and plasminogen concentrations in tissue eluates.
Main Results:
- No correlation between Lp(a) and plasminogen was observed in aortic intima.
- Plasminogen levels were relatively constant in thrombi, while Lp(a) levels varied significantly.
- Lp(a) was eluted from most intimal samples by epsilon-aca, indicating fibrin binding, but no direct relationship with plasminogen was found in eluates.
- A weak positive correlation between Lp(a) and plasminogen was paradoxically observed in thrombus eluates.
Conclusions:
- The findings do not support the hypothesis that Lp(a) displaces plasminogen in vivo.
- The significant elution of Lp(a) by epsilon-aca suggests its atherogenicity may stem from preferential binding to fibrin.
- Preferential Lp(a) binding to fibrin could promote lipid accumulation in atherosclerotic lesions.
Abstract:
Thrombotic occlusion is the major cause of myocardial infarction (MI), and fibrin accumulation appears to play a significant role in development of atherosclerotic lesions. Any factor that reduces the lysis of fibrin may thus increase the risk of MI, and it has been suggested that this accounts for the atherogenicity of the lipoprotein variant Lp(a). The characteristic feature of Lp(a) is an apoprotein which is homologous with part of the plasminogen molecule, and experiments in vitro suggest that it interferes with uptake and activation of plasminogen on cell surfaces and fibrin. The presence of Lp(a) also seemed to offer an explanation for the apparent absence of plasminogen from 70-80% of intimal samples. We have compared the levels of Lp(a) and plasminogen in normal intima and atherosclerotic lesions. In aortic intima there was no relation between Lp(a) and plasminogen, which was absent in some samples with no Lp(a), and present in others with high levels. In intravascular thrombi plasminogen was present at a rather constant concentration (16.3 +/- 4.6 micrograms/100 mg wet tissue), whereas Lp(a) varied over a 100 fold range (0-104 micrograms/100 mg). Plasminogen binds to fibrin and is activated on the fibrin clot, so levels in extracts may not fully represent Lp(a)/plasminogen interactions. After extraction the residual tissues and thrombi were treated with 1 M epsilon-aminocaproic acid (epsilon-aca) to elute lysine-bound components. Lp(a) was eluted from all but one intimal sample, confirming previous findings on its binding to fibrin in lesions, but there was no relation between the amounts of Lp(a) and plasminogen in the tissue eluates. Paradoxically, in the thrombi there was a weak positive correlation between Lp(a) and plasminogen in epsilon-aca eluates (r = 0.504, P = 0.05). These results do not support the hypothesis that Lp(a) displaces plasminogen in vivo, but the large amount of Lp(a) eluted by epsilon-aca suggests that its atherogenicity resides in preferential binding to fibrin, leading to increased lipid accumulation in lesions.