Abstract MP47: Assessment Of Atherosclerosis In A Novel Transgenic Mouse Expressing Pathogenic Levels Of Human Lipoprotein(a)

Autor: Julia Assini, Chuce Xing, Justin Clark, Tasnim Reza, Robert Gros, Michael Boffa, Marlys L Koschinsky
Rok vydání: 2021
Předmět:
Zdroj: Arteriosclerosis, Thrombosis, and Vascular Biology. 41
ISSN: 1524-4636
1079-5642
DOI: 10.1161/atvb.41.suppl_1.mp47
Popis: Studying the role of elevated plasma levels of lipoprotein(a) (Lp(a)) in atherogenesis is challenging given that the LPA gene encoding apo(a) is absent in typical animal models. As such we created a novel transgenic mouse line expressing both human apolipoprotein(a) (apo(a)) and human apoB100 ((Tg(LPA +/0 ;APOB +/0 )) . The LPA transgene, assembled in the pLIV vector, produces a physiologically relevant 12-kringle apo(a) isoform. The APOB transgene contains the entire human APOB gene with a mutation preventing APOB editing. In our atherosclerosis model, male and female mice were injected weekly with an antisense oligonucleotide targeting the mouse LDL receptor (IONIS Pharmaceuticals), and fed a high-fat, high-cholesterol diet for 12 weeks. High plasma Lp(a) levels were observed in both male and female Tg(LPA +/0 ;APOB +/0 ) mice (219.0±11.9 and 133.7±12.1 mg/dL, respectively; n=12/group). Importantly, high levels of Lp(a) in plasma did not result in metabolic alterations, including differences in weight gain, energy expenditure, activity, RER, VO 2 /VCO 2 consumption/output, and glucose tolerance compared to Tg(APOB +/0 ) control mice. Both male and female Tg(LPA +/0 ;APOB +/0 ) and Tg(APOB +/0 ) mice exhibited enhanced proatherogenic lipoprotein profiles with the majority of the cholesterol and TG present in the VLDL and LDL fractions. Complex lesions developed in all transgenic mice, including large, lipid-rich necrotic cores, with overlying fibrous caps and intimal calcium deposition. Immunohistochemistry with a monoclonal apo(a) antibody revealed the presence of Lp(a) in the plaques of Tg(LPA +/0 ;APOB +/0 ) mice. Analysis of aortic sinus lesions revealed a 23% increase in total plaque area in female Tg(LPA +/0 ;APOB +/0 ) mice compared to female Tg(APOB +/0 ) mice (p=0.0836). Moreover, atherosclerotic plaques in female Tg(LPA +/0 ;APOB +/0 ) mice contained significantly more calcium deposition than female Tg( APOB +/0 ) mice (1.79±0.4% vs. 2.96 ±0.3% of total plaque area (pTg(LPA +/0 ;APOB +/0 ) mice will be required to uncover the unique contribution of Lp(a) to atherogenesis.
Databáze: OpenAIRE
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