Transgenic mice expressing human Lp(a) develop larger, more vulnerable, more calcified atherosclerotic plaques, an effect specific to females (Atherosclerosis 2023)

Original title: High levels of lipoprotein(a) in transgenic mice exacerbate atherosclerosis and promote vulnerable plaque features in a sex-specific manner

Atherosclerosis · 30 May 2023 · 6

Assini JM, Clark JR, Youssef A, Xing C, Doerfler AM, Park SH, Saxena L, Yaseen AB, Børen J, Gros R, Bao G, Lagor WR et al.

In a new transgenic mouse model expressing both human apolipoprotein(a) and apoB-100, achieving pathogenic plasma Lp(a) levels of 87-250 mg/dL, mice were fed a high-fat, high-cholesterol diet for 12 weeks with Ldlr knocked down by antisense oligonucleotide. Compared with apoB-100-only controls, female Lp(a) transgenic mice developed larger aortic sinus plaques (+22%), bigger necrotic cores (+25%), and more calcification (+65%), along with less organised collagen, 42% higher oxidised phospholipid staining, and a 3.1-fold higher level of the proinflammatory cytokine MCP-1; these differences were not observed in males. The findings establish a robust animal model demonstrating that Lp(a) drives more severe, vulnerable atherosclerotic lesions in a sex-specific manner, with a stronger pro-inflammatory phenotype in females.

Original abstract

Background And Aims: Despite increased clinical interest in lipoprotein(a) (Lp(a)), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic cardiovascular disease. Existing murine transgenic (Tg) Lp(a) models are limited by low plasma levels of Lp(a) and have not consistently shown a pro-atherosclerotic effect of Lp(a).

Methods: We generated Tg mice expressing both human apolipoprotein(a) (apo(a)) and human apoB-100, with pathogenic levels of plasma Lp(a) (range 87-250 mg/dL). Female and male Lp(a) Tg mice (Tg(LPA+/0;APOB+/0)) and human apoB-100-only controls (Tg(APOB+/0)) (n = 10-13/group) were fed a high-fat, high-cholesterol diet for 12 weeks, with Ldlr knocked down using an antisense oligonucleotide. FPLC was used to characterize plasma lipoprotein profiles. Plaque area and necrotic core size were quantified and immunohistochemical assessment of lesions using a variety of cellular and protein markers was performed.

Results: Male and female Tg(LPA+/0;APOB+/0) and Tg(APOB+/0) mice exhibited proatherogenic lipoprotein profiles with increased cholesterol-rich VLDL and LDL-sized particles and no difference in plasma total cholesterol between genotypes. Complex lesions developed in the aortic sinus of all mice. Plaque area (+22%), necrotic core size (+25%), and calcified area (+65%) were all significantly increased in female Tg(LPA+/0;APOB+/0) mice compared to female Tg(APOB+/0) mice. Immunohistochemistry of lesions demonstrated that apo(a) deposited in a similar pattern as apoB-100 in Tg(LPA+/0;APOB+/0) mice. Furthermore, female Tg(LPA+/0;APOB+/0) mice exhibited less organized collagen deposition as well as 42% higher staining for oxidized phospholipids (OxPL) compared to female Tg(APOB+/0) mice. Tg(LPA+/0;APOB+/0) mice had dramatically higher levels of plasma OxPL-apo(a) and OxPL-apoB compared to Tg(APOB+/0) mice, and female Tg(LPA+/0;APOB+/0) mice had higher plasma levels of the proinflammatory cytokine MCP-1 (+3.1-fold) compared to female Tg(APOB+/0) mice.

Conclusions: These data suggest a pro-inflammatory phenotype exhibited by female Tg mice expressing Lp(a) that appears to contribute to the development of more severe lesions with greater vulnerable features.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.