Lipoprotein(a) accelerates atherosclerosis in uremic mice

Area of Science:

• Cardiovascular Research
• Nephrology
• Atherosclerosis Research

Background:

• Uremic patients exhibit elevated plasma lipoprotein(a) [Lp(a)] levels, increasing cardiovascular disease (CVD) risk.
• Lipoprotein(a) comprises apolipoprotein(a) [apo(a)] disulfide-bound to apolipoprotein B-100 (apoB) and binds oxidized phospholipids (OxPL).
• Uremia exacerbates lipoprotein-associated OxPL, potentially making Lp(a) more atherogenic in this context.

Purpose of the Study:

• To investigate if transgenic (Tg) expression of human Lp(a) exacerbates atherosclerosis in a mouse model of uremia.
• To determine the role of apo(a) and Lp(a) in atherosclerosis development under uremic conditions.

Main Methods:

• Induction of moderate uremia via 5/6 nephrectomy (NX) in Tg mice expressing human apo(a), apoB-100, or Lp(a), alongside wild-type (WT) controls.
• Administration of a high-fat diet for 35 weeks post-NX.
• Assessment of aortic root atherosclerotic plaque area and plasma oxidized phospholipids (OxPL) using the E06 antibody.

Main Results:

• Transgenic expression of apoB-100 and Lp(a) led to increased LDL-cholesterol.
• Aortic root atherosclerosis was significantly increased in apo(a)-Tg (1.8-fold) and Lp(a)-Tg (3.3-fold) mice compared to WT controls.
• Plasma OxPL levels correlated with the presence of apo(a) and Lp(a).

Conclusions:

• Transgenic expression of apo(a) or Lp(a) significantly increased atherosclerosis in uremic mice.
• The binding of OxPL to apo(a) and Lp(a) may be a key mechanism contributing to the heightened atherogenicity of Lp(a) in uremia.
• These findings highlight Lp(a) as a critical factor in cardiovascular risk associated with chronic kidney disease.