Cadi > Topic > Lipoprotein(a) > Mechanism of Action

Mechanism of Action

Mechanism of Action 

  • Elevated Lp(a) levels can increase the risk of CVD (cardiovascular disease) (i) via prothrombotic/anti-fibrinolytic effects by virtue of structural homology of apolipoprotein(a) (apo(a)) with plasminogen, (ii) via accelerated atherogenesis as a result of intimal deposition of Lp(a)-cholesterol, or both and (iii) via proinflammatory properties.1, 2 Thus, the atherosclerosis is mediated through its LDL component and thrombosis through its apo(a) component.
  • Apolipoprotein(a) shares homology with plasminogen but has no fibrinolytic activity and may adversely affect fibrinolysis.3-5 Lp(a) may be the only risk factor that promotes both plaque buildup and abnormal blood clotting, the two features most responsible for heart attacks. The presence of apo(a) attached to LDL turns Lp(a) ten times more dangerous than LDL.5-7
  • Lp(a) is a major carrier of oxidized phospholipids and Lp-PLA2. Lp(a) serves as a scavenger and carrier of oxidized phospholipids and this functional property may be responsible for the proatherogenic and proinflmatory effects of Lp(a). Lp(a) avidly bind proinflammatory oxidized phospholipids (OxPL)  and therefore is particularly enriched in OxPL.6, 8 Therefore, these 2 parameters highly correlated when measured in blood and provide additive information. The correlation between OxPL and Lp(a) is strongest when Lp(a) levels were high in the setting of small apo(a) isoforms.6, 9, 10
  • Because most patients (80%) have 2 distinct apo(a) isoforms and since the Lp(a) levels and the OxPL/apoB measures reflect the net effect of these factors, it is possible the OxPL/apoB measure may closely reflect the cumulative atherogenicity of small Lp(a) particles. A Mayo Clinic study has demonstrated that OxPL/apoB was an independent predictor of the presence of angiographically defined CAD (coronary artery disease) in a multivariable adjusted model that also contained Lp(a) levels.11

Sources

1. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. Oct 21 2010.

2. McLean JW, Tomlinson JE, Kuang WJ, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987;330(6144):132-137.

3. Sandholzer C, Hallman DM, Saha N, et al. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Hum Genet. 1991;86(6):607-614.

4. Jha P, Enas E, Yusuf S. Coronary Artery Disease in Asian Indians: Prevalence and Risk Factors. Asian Am Pac Isl J Health. Autumn 1993;1(2):163-175.

5. Enas EA, Chacko V, Senthilkumar A, Puthumana N, Mohan V. Elevated lipoprotein(a)–a genetic risk factor for premature vascular disease in people with and without standard risk factors: a review. Dis Mon. Jan 2006;52(1):5-50.

6. Tsimikas S, Clopton P, Brilakis ES, et al. Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size, and cardiovascular risk factors: results from the Dallas Heart Study. Circulation. Apr 7 2009;119(13):1711-1719.

7. Tsimikas S, Tsironis LD, Tselepis AD. New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arterioscler Thromb Vasc Biol. Oct 2007;27(10):2094-2099.

8. Tsimikas S, Witztum JL. The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol. Aug 2008;19(4):369-377.

9. Hobbs HH, White AL. Lipoprotein(a): intrigues and insights. Curr Opin Lipidol. 1999;10(3):225-236.

10. Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol. Sep 14 2010;56(12):946-955.

11. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. Jul 7 2005;353(1):46-57.

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