Lipoprotein(a) accelerates atherosclerosis in uremic mice.
Uremic patients have increased plasma lipoprotein(a) [Lp(a)] levels and elevated risk of cardiovascular disease. Lp(a) is a subfraction of LDL, where apolipoprotein(a) [apo(a)] is disulfide bound to apolipoprotein B-100 (apoB). Lp(a) binds oxidized phospholipids (OxPL), and uremia increases lipoprotein-associated OxPL. Thus, Lp(a) may be particularly atherogenic in a uremic setting. We therefore investigated whether transgenic (Tg) expression of human Lp(a) increases atherosclerosis in uremic mice. Moderate uremia was induced by 5/6 nephrectomy (NX) in Tg mice with expression of human apo(a) (n = 19), human apoB-100 (n = 20), or human apo(a) + human apoB [Lp(a)] (n = 15), and in wild-type (WT) controls (n = 21). The uremic mice received a high-fat diet, and aortic atherosclerosis was examined 35 weeks later. LDL-cholesterol was increased in apoB-Tg and Lp(a)-Tg mice, but it was normal in apo(a)-Tg and WT mice. Uremia did not result in increased plasma apo(a) or Lp(a). Mean atherosclerotic plaque area in the aortic root was increased 1.8-fold in apo(a)-Tg (P = 0.025) and 3.3-fold (P = 0.0001) in Lp(a)-Tg mice compared with WT mice. Plasma OxPL, as detected with the E06 antibody, was associated with both apo(a) and Lp(a). In conclusion, expression of apo(a) or Lp(a) increased uremia-induced atherosclerosis. Binding of OxPL on apo(a) and Lp(a) may contribute to the atherogenicity of Lp(a) in uremia.
Pedersen
Tanja X
TX
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. tanjax@sund.ku.dk
McCormick
Sally P
SP
Tsimikas
Sotirios
S
Bro
Susanne
S
Nielsen
Lars B
LB
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D014511:Uremia / Q000150:complications* / Q000378:metabolism
D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D010743:Phospholipids; C099252:oxidized low density lipoprotein