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

activation of plasminogen and apolipoproteins - apo(a)

The major apolipoproteins present in Lp(a) -- the apolipoprotein B or apoB series and the apolipoprotein(a) or apo(a) series -- play different roles in health and disease. ApoB-100 is the portion of the Lp(a) molecule (the ligand) that is recognized by the receptor. Other lipid and apolipoprotein components vary considerably in the LDL complex, but they all interact to maintain the apo B molecule in a specific spatial orientation for receptor binding. The second major Lp(a) apolipoprotein is apo(a), which has been described as a giant mutant of plasminogen. This is because approximately 80% of the amino acid sequence of apo(a) is identical to that of plasminogen. Because of this homology, apo(a) is able to competitively inhibit the surface binding and activation of plasminogen. Blocking plasminogen activation prevents the formation of plasmin, a crucial component in clot lysis. Plasmin is also involved in the activation of a compound referred to as latent transforming growth factor-b (TGF-b), a potent inhibitor of smooth muscle cell growth in the vascular endothelium.
source:Grainger DJ et al. Science

Apolipoproteins and Heart Disease

Lipoprotein(a), or Lp(a), is a lipid-protein complex involved in the transport of cholesterol in the circulation. Scandinavian researchers reported in 1963 that men with high levels of Lp(a) were more susceptible to coronary artery disease (CAD) than men with low levels. Unfortunately, these findings were ignored for more than 20 years because of difficulties in testing for Lp(a). Then 8 years ago, American researchers began reexamining Lp(a). They have since found that a high plasma concentration of Lp(a) is a major risk factor for atherosclerotic and thrombotic vascular disease -- including CAD, myocardial infarction, restenosis of coronary artery grafts, carotid atherosclerosis, and stroke -- and that this risk is independent of age, diet, physical activity, smoking status, ethanol consumption, and sex. Population studies indicate that abnormal plasma levels of Lp(a) may cause up to 25% of premature MIs. Elevated levels of Lp(a) are also associated with significant carotid atherosclerosis, even in the absence of clinical heart disease.
source:Schreiner PJ et al. Arterioscler Thromb.

apolipoprotein studies related to cardiovascular disease

Despite advances in diagnosis, care, and treatment, cardiovascular disease remains the number one killer in the United States and throughout the industrialized world. CAD is particularly common in males, even those less than 50 years old, and in many cases there are no clear risk factors other than a family history of heart disease. Hypercholesterolemia, for example, accounts for less than half of all MIs in the United States. Continuing research on the structure, function, pathophysiology, and heritability of apolipoproteins should lead to improvements in diagnosis, risk assessment, and treatment of cardiovascular and also cerebrovascular diseases.

apolipoprotein E gene polymorphism

Van Bockxmeer and Mamotte studied apolipoprotein E gene polymorphism in 91 Australian men 3--50 years of age with confirmed symptomatic coronary obstructive CAD who had been referred for coronary angioplasty. Each patient had at least one coronary artery with more than 50% luminal diameter obstruction (averaged from multiple views). Patients were compared with 172 healthy men. Five of the 19 CAD patients who were less than 40 years of age were homozygous for the e4 allele, representing a 16-fold increase in prevalence compared with controls. In CAD patients aged 40-50 years, e4 allele frequency was 60% higher than in controls. Moreover, CAD patients homozygous for e4 were 5 years younger, on average, than men with other genotypes (e.g., e3/e4). "Inheritance of e4 seems to confer risk of premature ischemic heart disease in males, homozygotes being especially at risk at a younger age," concluded the investigators.
source:Van Bockxmeer FM, Mamotte CDS. Lancet

Genetics, Apolipoprotein E, and Heart Disease

Apolipoprotein E (apoE) is a lipid-protein complex that plays a role in the pathogenesis of heart disease. Apo E is a protein constituent of very-low-density lipoprotein (VLDL) and chylomicrons. It is believed to mediate clearing of these lipoproteins from the circulation through specific VLDL binding to cell surface receptors, and thus it plays an important role in plasma lipid metabolism. The apoE gene is polymorphic; that is, the DNA base sequence varies slightly so that the apoE proteins produced differ from each other in just one amino acid. This substitution can lead to considerable differences in activity. The three common apoE proteins -- apoE2, apoE3, and apoE4 -- are coded for by three common genes (alleles) designated e2, e3, and e4. According to biochemists Van Bockxmeer and Mamotte, at a popula-tion level the most significant determinant of plasma lipoprotein levels found to date is polymorphism in the apoE gene.
ApoE2 has a reduced affinity for the cellular receptor, so e2/e2 carriers (homozygotes) have elevated lipids in the blood, and in 5% of cases this manifests itself as type III hyperlipidemia. The e4 allele is associated with higher total and LDL cholesterol levels. Certain populations with a high incidence of CAD (e.g., Finns) have been shown to have high serum cholesterol levels and an increased frequency of e4, while populations with a low incidence of CAD and low cholesterol levels (e.g., Orientals) have a low frequency of e4. A lower e4 frequency has been reported in octogenarians, suggesting that individuals who are free of the e4 allele are the ones who survive long enough to become octogenarians.
source:Wenham PR et al. Atherosclerosis.