Abstract
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.
Highlights
Chronic kidney disease markedly accelerates atherosclerosis and is a potent risk factor of cardiovascular death [1]
We have recently documented that the pro-atherogenic effect of uremia in 5/6 NX mice includes increased levels of oxidized phospholipids (OxPL) on mouse apolipoprotein B-100 (apoB) particles and increased formation of autoantibodies to oxidized low-density lipoprotein (LDL) (OxLDL) [8, 9]
Moderate uremia was not associated with increased apo(a) or Lp(a) levels in these transgenic mouse models
Summary
Chronic kidney disease markedly accelerates atherosclerosis and is a potent risk factor of cardiovascular death [1]. Recent clinical trials have shown that lowering low-density lipoprotein (LDL) with statins does not reduce cardiovascular risk in dialysis patients [2, 3]. This underscores the need to investigate unique mechanisms causing accelerated atherosclerosis in this patient group. The putative pro-atherogenic ability of Lp(a) to bind OxPL may be important in conditions associated with increased oxidative stress, such as uremia. It remains to be established whether Lp(a) plays a causal role in development of uremic atherosclerosis
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