An Apolipoprotein(a) Peptide Delays Chylomicron Remnant Clearance and Increases Plasma Remnant Lipoproteins and Atherosclerosis In Vivo

Abstract

Objective-Humans with high expression of apolipoprotein(a) [apo(a)] and high plasma levels of lipoprotein(a) [Lp(a)] are at increased risk for atherosclerosis, but the mechanism is not known. We have previously shown that the KIV 5-8 domain of apo(a) has unique cell-surface binding properties, and naturally occurring fragments of apo(a) encompassing this domain are thought to be atherogenic in humans. To investigate the effect of KIV 5-8 on lipoprotein metabolism and atherosclerosis in vivo, we created several independent lines of liver-targeted KIV 5-8 transgenic mice. Methods and Results-The transgenic mice have plasma apo(a) peptide concentrations that are similar to Lp(a) concentrations in humans at risk for coronary artery disease. Remarkably, the transgenic mice had a 2-to 4-fold increase in cholesterol-rich remnant lipoproteins (RLPs) when fed a cholesterol-rich diet, and a 5-to 20-fold increase in atherosclerosis lesion area in the aortic root. Using an in vivo clearance study, we found only slight differences in the triglyceride and apolipoprotein B secretion rates between the 2 groups of mice, suggesting an RLP clearance defect.Using an isolated perfused mouse liver system, we showed that transgenic livers had a slower rate of RLP removal, which was retarded further when KIV 5-8 , full-length apo(a), or Lp(a) were added to the perfusate. An apo(a) peptide that does not interact with cells, K(IV 2 ) 3 , did not retard RLP removal, and low-density lipoprotein (LDL) had a much smaller effect than Lp(a). Conclusions-We propose that high levels of apo(a)/Lp(a), perhaps acting via a specific cell-surface binding domain, inhibit hepatic clearance of remnants, leading to high plasma levels of RLPs and markedly enhanced atherosclerosis. We speculate that the KIV 5-8 region of apo(a) competes with one or more receptors for remnant clearance in the liver and that this process may represent one mechanism accounting for increased atherosclerosis in humans with high secretion levels of apo(a) [apo(a)] is attached covalently to the apolipoprotein B100 (apoB100) of LDL. 1,2 Apo(a) can also be noncovalently associated with the apoB of very-low-density lipoprotein (VLDL) and remnant lipoproteins (RLPs). [3][4][5] Apo(a) is made up of variable numbers of protein domains called kringles, designated KIV 1 through KIV 10 ( Figure I, available online http://atvb.ahajournals.org). 6 Interest in apo(a)-containing lipoproteins arises from the finding that high plasma levels of Lp(a) are an independent risk factor for atherothrombotic coronary artery disease and stroke. 7,8 Postulated mechanisms include apo(a)-mediated inhibition of plasmin activation on fibrin, stimulation of smooth muscle cell proliferation and migration, increased retention of Lp(a) in the arterial wall, and alterations in endothelial function. 9 -11 Although studies in mice have supported these mechanisms, none has been shown to be directly responsible for the increased risk of coronary artery or cerebrovascular disease in humans..Previous studies ...

A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma

“…1.075, whereas apoB-100 is present throughout the expected range. There is also a small amount of apo [a] in the VLDL range, which has been documented in other studies (31), that does not appear to have much associated OxPL.…”

Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice

“…27 In fact, up to 4% of apo(a) is present on verylow-density lipoprotein particles, and these complexes may have a slower catabolism. 28,29 In contrast, the clearance of Lp(a) is less well understood. The preponderance of evidence suggests that the LDL receptor does not play a major role in Lp(a) clearance.…”

Elements in the C terminus of apolipoprotein [a] responsible for the binding to the tenth type III module of human fibronectin

“…Moreover, a recombinant form of KV has been reported to exhibit an antiangiogenic function (32). Very recently in mouse models, the KIV-5 to -8 peptide was implicated in the delayed chylomicron remnant removal from the plasma and also immunochemically identified in the atherosclerotic area of the aortic root examined (33). The PD has received relatively little attention, being functionally inert from an enzymatic standpoint, although recently it was shown to be one of the elements involved in the binding of human apo[a] to fibrinogen (34).…”