In vivo fate and scavenger receptor recognition of oxidized lipoprotein[a] isoforms in rats.
High levels of Lp[a] in blood form an independent risk factor for atherosclerosis. Oxidative modification of Lp[a] may be involved in the suggested atherogenic action of Lp[a]. After Cu(2+)-mediated oxidative modification of the 440 kDa and 610 kDa apo[a] isoforms of lipoprotein[a] (Ox-Lp[a]), the in vivo fate was investigated in rats. Ox-Lp[a], when injected into rats, was rapidly removed from the blood circulation by the liver, in which the intrahepatic fate is dependent on the degree of oxidation of the isoforms. Upon oxidation to a slightly increased negative charge of Lp[a], the high molecular weight form of Lp[a] is recognized more efficiently by the Kupffer cells than by the endothelial cells. When the liver uptake of Ox-Lp[a] is blocked by preinjection of polyinosinic acid (poly I), the association of Ox-Lp[a] with the rat heart is increased 20-fold. In vitro studies show that the association and degradation of 125I-labeled Ox-Lp[a] with liver endothelial and Kupffer cells was inhibited by oxidized LDL (Ox-LDL), poly I, or Ox-Lp[a] itself by 60-90%, while only a partial competition was found with acetylated-LDL (up to 25%). In conclusion, after oxidative modification of Lp[a], there is recognition of Ox-Lp[a] by specific oxidized-lipoprotein receptors on liver endothelial and Kupffer cells; the relative importance at low degrees of oxidation of Lp[a] is dependent on the molecular weight of the apo[a] isoforms. Under conditions in which liver uptake is not adequate, the deposition of Ox-Lp[a] in the heart may be of potential pathological importance.
de Rijke
Y B
YB
Division of Biopharmaceutics, Sylvius Laboratory, University of Leiden, The Netherlands.
Jürgens
G
G
Hessels
E M
EM
Hermann
A
A
van Berkel
T J
TJ
D000818:Animals; D001667:Binding, Competitive; D003300:Copper / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D007700:Kinetics; D007728:Kupffer Cells / Q000378:metabolism; D017270:Lipoprotein(a) / Q000097:blood* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D011069:Poly I / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018110:Receptors, Lipoprotein
D017270:Lipoprotein(a); D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; D011069:Poly I; D003300:Copper