apolipoproteins in the pathogenesis of atherosclerosis

Recently an international research team described the results of their studies of Lp(a) and apo(a) in the pathogenesis of atherosclerosis. They found that both substances promote vascular smooth muscle cell proliferation and migration, one of the hallmarks of atherosclerosis. Grainger et al. (Cambridge University) and Lawn et al. (Stanford University) cultured smooth muscle cells from healthy human arteries, and then exposed them to Lp(a) and purified apo(A). They found that both Lp(a) and apo(a) -- but not LDL -- caused a dose-dependent acceleration of vascular smooth muscle cell proliferation. They also found that cell-associated plasmin activity was reduced to one seventh the control level by Lp(a) and to one fifth the control level by apo(a) in both human and rat vascular smooth muscle cell cultures. Moreover, Lp(a) and apo(a) both reduced the amount of active TGF-b to 1/100 the level in control (LDL-treated) cultures. Finally, the addition of plasmin to Lp(a)-treated vascular smooth muscle cell cultures overcame the effects of Lp(a) and reduced growth rates to control levels. These results all suggest that the acceleration in smooth muscle cell proliferation is indeed due to the ability of Lp(a) and apo(a) to competitively inhibit the cleavage of plasminogen, reducing plasmin concentrations and TGF-b activation.

Thus, the homology of apo(a) with plasminogen, with subsequent inhibition of plasminogen activation, contributes to atherosclerotic plaque formation by two mechanisms: it prevents the activation of TGF-b, allowing smooth muscle cells to proliferate, and it prevents clot lysis, adding fibrin and other debris to growing atherosclerotic plaque. In addition, Lp(a) binds endothelial and macrophage cells and fibrin, and deposits its cholesterol load and other fatty debris in the vascular endothelium, another hallmark of atherosclerosis. "Both inhibition of clot lysis and enhancement of cell migration could contribute to the process of atherogenesis," concluded the Cambridge and Stanford researchers. "We suggest that Lp(a) may contribute to the growth of the arterial lesions of atherosclerosis by promoting the proliferation of vascular smooth muscle cells."
source:Grainger DJ et al. Science. 1993; 260: 1655- 1658