Published online before print May 19, 2005, doi: 10.1161/01.ATV.0000170819.57945.03
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
An Apolipoprotein(a) Peptide Delays Chylomicron Remnant Clearance and Increases Plasma Remnant Lipoproteins and Atherosclerosis In Vivo
From the Departments of Medicine (C.M.D., G.K., C.K., L.S.H., I.T.) and Anatomy & Cell Biology (I.T.) and Physiology & Cellular Biophysics (I.T.), Columbia University, New York, NY; the Division of Food Science (S.J.L.), College of Life and Environmental Sciences, Korea University, Seoul, Korea; the Department of Medicine (S.J.L., I.G., A.D.C.), Stanford University School of Medicine, Stanford, Calif; the Palo Alto Medical Foundation (A.D.C.), Palo Alto, Calif; and the Department of Biochemistry (C.S., L.B., M.L.K.), Queen’s University, Kingston, Ontario, Canada.
Correspondence to Dr Ira Tabas, Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032. E-mail iat1{at}columbia.edu
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 KIV5–8 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 KIV5–8 on lipoprotein metabolism and atherosclerosis in vivo, we created several independent lines of liver-targeted KIV5–8 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 KIV5–8, full-length apo(a), or Lp(a) were added to the perfusate. An apo(a) peptide that does not interact with cells, K(IV2)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 KIV5–8 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).
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 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 KIV5–8 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).
Key Words: apolipoprotein(a) • atherosclerosis • hepatic clearance • lipoprotein(a) • remnant lipoproteins
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