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Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis

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Abstract

Lipoprotein(a) [Lp(a)], comprised of apolipoprotein(a) [apo(a)] and a low-density lipoprotein-like particle, is a genetically determined, causal risk factor for cardiovascular disease and calcific aortic valve stenosis. Lp(a) is the major plasma lipoprotein carrier of oxidized phospholipids, is pro-inflammatory, inhibits plasminogen activation, and promotes smooth muscle cell proliferation, as defined mostly through in vitro studies. Although Lp(a) is not expressed in commonly studied laboratory animals, mouse and rabbit models transgenic for Lp(a) and apo(a) have been developed to address their pathogenicity in vivo. These models have provided significant insights into the pathophysiology of Lp(a), particularly in understanding the mechanisms of Lp(a) in mediating atherosclerosis. Studies in Lp(a)-transgenic mouse models have demonstrated that apo(a) is retained in atheromas and suggest that it promotes fatty streak formation. Furthermore, rabbit models have shown that Lp(a) promotes atherosclerosis and vascular calcification. However, many of these models have limitations. Mouse models need to be transgenic for both apo(a) and human apolipoprotein B-100 since apo(a) does not covalently associated with mouse apoB to form Lp(a). In established mouse and rabbit models of atherosclerosis, Lp(a) levels are low, generally <20 mg/dL, which is considered to be within the normal range in humans. Furthermore, only one apo(a) isoform can be expressed in a given model whereas over 40 isoforms exist in humans. Mouse models should also ideally be studied in an LDL receptor negative background for atherosclerosis studies, as mice don’t develop sufficiently elevated plasma cholesterol to study atherosclerosis in detail. With recent data that cardiovascular disease and calcific aortic valve stenosis is causally mediated by the LPA gene, development of optimized Lp(a)-transgenic animal models will provide an opportunity to further understand the mechanistic role of Lp(a) in atherosclerosis and aortic stenosis and provide a platform to test novel therapies for cardiovascular disease.

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Authors and Affiliations

  1. Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California, La Jolla, San Diego, CA, USA

    Calvin Yeang, Bruno Cotter & Sotirios Tsimikas

  2. Vascular Medicine Program, University of California San Diego, 9500 Gilman Dr., BSB 1080, La Jolla, San Diego, CA, 92093-0682, USA

    Sotirios Tsimikas

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  1. Calvin Yeang
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  2. Bruno Cotter
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Correspondence to Sotirios Tsimikas.

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NIH R01-HL119828, P01-HL088093, P01 HL055798, R01-HL106579, R01-HL078610, R01-HL124174.

Disclosures

Dr. Tsimikas is a co-inventor of and receive royalties from patents owned by the University of California San Diego on oxidation-specific antibodies. Dr. Tsimikas has a dual appointment at UCSD and as an employee at Isis Pharmaceuticals, Inc. The other authors report no conflicts.

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Yeang, C., Cotter, B. & Tsimikas, S. Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis. Cardiovasc Drugs Ther 30, 75–85 (2016). https://doi.org/10.1007/s10557-015-6634-1

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