H11-Alb-hLPA Mice

Catalog Number: C001542

Strain Name: C57BL/6NCya-Igs2em1(Alb-hLPA)/Cya

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

 

Strain Description

Lipoprotein(a) (Lp(a)) is a lipoprotein particle consisting of apolipoprotein(a) (Apo(a)) bound to low-density lipoprotein (LDL) containing apolipoprotein B (ApoB), where the LPA gene encoding for Apo(a) is only found in the genomes of humans and some non-human primates. LP(a) is similar in size and lipid content to low-density lipoprotein (LDL) and is considered a new risk factor for several cardiovascular diseases (CVD), including atherosclerosis, coronary heart disease, and stroke [1]. Lp(a) differs from LDL in that it contains an additional variable-length Apo(a), which covalently binds to ApoB-100 via a single disulfide bond. Lp(a) plays a crucial role in systemic lipid transport, guiding inflammatory cells into blood vessel walls and promoting smooth muscle cell proliferation. Additionally, it participates in wound healing and tissue repair, interacting with components of the blood vessel wall and extracellular matrix [2]. However, Lp(a) can also cause arterial narrowing by adhering to the arterial wall, accelerating blood clot formation, and triggering pathological changes related to coronary heart disease, atherosclerosis, thrombosis, and stroke [3]. The plasma concentration of Lp(a) is closely related to genetic factors, primarily regulated by the LPA gene. Consequently, the LPA gene represents an important potential target for cardiovascular disease treatment. Currently, several novel therapies aimed at modulating LPA gene transcription rates are under development, including small interfering RNA (siRNA) and antisense oligonucleotide (ASO) drugs [4]. Given that the LPA gene is expressed only in humans and some non-human primates but not in mice, constructing a mouse model expressing the human LPA gene is crucial for the preclinical evaluation of lipid-lowering drugs.

The H11-Alb-hLPA mouse is a humanized model where the human LPA protein coding sequence (CDS) is integrated into the mouse H11 safe harbor locus. In this model, the human LPA gene is specifically expressed in the liver under the control of the mouse Alb promoter. It can be used to study the pathogenic mechanisms of the LPA gene in hyperlipidemia and related cardiovascular diseases, as well as to evaluate targeted drug development. Additionally, Cyagen has developed a conditionally inducible LPA humanization model (catalog number: C001521) using the CAG promoter. When crossed with Alb-Cre mice (liver-specific Cre mice), the resulting LPA-humanized mice (catalog number: C001522) exhibit significantly higher LPA protein levels compared to the H11-Alb-hLPA mice. Therefore, researchers please choose the appropriate mouse strain based on their specific requirements for LPA protein expression levels and genetic characteristics.

Strain Strategy

The “Alb promoter-Kozak-Human LPA CDS-WPRE-rBG pA” cassette was inserted into the H11 locus (~0.7 kb 5' of Eif4enif1 gene and ~4.5 kb 3' of the Drg1 gene).


Application

  • Research on atherosclerosis, hyperlipidemia, thrombotic cardiovascular diseases, etc.;
  • Preclinical evaluation of human LPA-targeted drugs.

Validation Data

1. Detection of human LPA gene expression

Figure 1. Human LPA gene expression in the livers of 11-week-old male H11-Alb-hLPA mice and wild-type (WT) mice. RT-qPCR results demonstrate specific expression of the human LPA gene in the liver of H11-Alb-hLPA mice, while the liver of wild-type mice does not express the human LPA gene.

2. Detection of human LPA protein expression

Figure 2. ELISA detection of human LPA protein expression in serum of male and female H11-Alb-hLPA mice at 6-11 weeks of age* (♂ n=5; ♀ n=4). The results show that human LPA protein levels in the serum of H11-Alb-hLPA mice remain stable during this age range. Notably, male mice exhibit higher LPA protein expression than female mice, while the levels in female mice are relatively consistent compared to male mice. (Data presented as Mean±SEM.)

*This assay utilized the Human Lipoprotein A ELISA Kit from Abcam, product number ab212165.




References
[1]Kronenberg F. Lipoprotein(a). Handb Exp Pharmacol. 2022;270:201-232.
[2]Brown MS, Goldstein JL. Plasma lipoproteins: teaching old dogmas new tricks. Nature. 1987 Nov 12-18;330(6144):113-4.
[3]Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Lipoprotein(a) and risk of myocardial infarction--genetic epidemiologic evidence of causality. Scand J Clin Lab Invest. 2011 Apr;71(2):87-93.
[4]Alebna, P. L., & Mehta, A. (2023, September 19). An Update on Lipoprotein(a): The Latest on Testing, Treatment, and Guideline Recommendations. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2023/09/19/10/54/an-update-on-lipoprotein-a