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

Autor: Assini JM; Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada., Clark JR; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, N6A 5B7, Canada., Youssef A; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada., Xing C; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada., Doerfler AM; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA., Park SH; Department of Bioengineering, Rice University, Houston, USA., Saxena L; Department of Bioengineering, Rice University, Houston, USA., Yaseen AB; Department of Bioengineering, Rice University, Houston, USA., Børen J; Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden., Gros R; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, N6A 5B7, Canada., Bao G; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada., Lagor WR; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Department of Bioengineering, Rice University, Houston, USA., Boffa MB; Department of Biochemistry, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, N6A 5B7, Canada; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada. Electronic address: mlk@robarts.ca., Koschinsky ML; Robarts Research Institute, Schulich School of Medicine & Dentistry, London, Ontario, Canada; Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, N6A 5B7, Canada. Electronic address: mboffa@uwo.ca.
Jazyk: angličtina
Zdroj: Atherosclerosis [Atherosclerosis] 2023 Nov; Vol. 384, pp. 117150. Date of Electronic Publication: 2023 May 30.
DOI: 10.1016/j.atherosclerosis.2023.05.019
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marlys L. Koschinsky has held a research grant from Pfizer; is a member of advisory boards for Amya Therapeutics and Novartis; has received speaker's honoraria/consulting fees from Amgen, Regeneron, and Eli Lilly; and holds/has held research contracts with Sanofi, Ionis, Eli Lilly, and Abcentra. Michael B. Boffa has held a research contract with Ionis.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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