Identification of genomic loci regulating platelet plasminogen activator inhibitor-1 in mice

被引：2
作者：
Siebert, Amy E.
Brake, Marisa A.
Verbeek, Stephanie C.
Johnston, Alexander J.
Morgan, Andrew P. [1 ]
Cleuren, Audrey C. [2 ]
Jurek, Adrianna M.
Schneider, Caitlin D.
Germain, Derrik M.
Battistuzzi, Fabia U. [3 ,4 ]
Zhu, Guojing [2 ]
Miller, Darla R. [5 ,6 ]
Johnsen, Jill M. [7 ]
Villena, Fernando Pardo-Manuel de
Rondina, Matthew T. [8 ,9 ,10 ,11 ]
Westrick, Randal J. [12 ,13 ,14 ,15 ]
机构：
[1] Oakland Univ, Dept Biol Sci, Rochester, MI USA
[2] Duke Univ, Sch Med, Dept Med, Durham, NC USA
[3] Univ Michigan, Life Sci Inst, Ann Arbor, MI USA
[4] Oakland Univ, Dept Bioengn, Rochester, MI 48063 USA
[5] Oakland Univ, Ctr Data Sci & Big Data Analyt, Rochester, MI USA
[6] Oakland Univ, Ctr Biomed Res, Rochester, MI USA
[7] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC USA
[8] Univ Washington, Inst Stem Cell & Regenerat Med, Dept Med, Seattle, WA USA
[9] Univ Washington, Ctr Cardiovasc Biol, Seattle, WA USA
[10] Univ Utah, Dept Internal Med, Mol Med Program, Salt Lake City, UT USA
[11] Univ Utah, Dept Pathol, Mol Med Program, Salt Lake City, UT USA
[12] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT 84148 USA
[13] Oakland Univ, Eye Res Ctr, William Beaumont Sch Med, Rochester, MI USA
[14] Oakland Univ, Dept Fdn Med Studies, William Beaumont Sch Med, Rochester, MI USA
[15] Oakland Univ, Dept Biol Sci, 305 Dodge Hall,118 Lib Dr, Rochester, MI 48309 USA
来源：
JOURNAL OF THROMBOSIS AND HAEMOSTASIS | 2023年 / 21卷 / 10期
基金：
美国国家卫生研究院;
关键词：
USA; GENE DEFICIENT MICE; VASCULAR THROMBOSIS; PAI-1; DEFICIENCY; EXPRESSION; MUTATION; PLASMA; TYPE-1; MEGAKARYOCYTE; GENERATION; PROTEINS;
D O I：
10.1016/j.jtha.2023.06.018
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
Background: Plasminogen activator inhibitor-1 (PAI-1, Serpine1) is an important circulating fibrinolysis inhibitor. PAI-1 exists in 2 pools, packaged within platelet alpha-granules and freely circulating in plasma. Elevated plasma PAI-1 levels are associated with cardiovascular disease. However, little is known about the regulation of platelet PAI-1 (pPAI-1).Objectives: We investigated the genetic control of pPAI-1 levels in mice and humans.Methods: We measured pPAI-1 antigen levels via enzyme-linked immunosorbent assay in platelets isolated from 10 inbred mouse strains, including LEWES/EiJ (LEWES) and C57BL/6J (B6). LEWES and B6 were crossed to produce the F1 generation, B6LEW-ESF1. B6LEWESF1 mice were intercrossed to produce B6LEWESF2 mice. These mice were subjected to genome-wide genetic marker genotyping followed by quantitative trait locus analysis to identify pPAI-1 regulatory loci.Results: We identified differences in pPAI-1 between several laboratory strains, with LEWES having pPAI-1 levels more than 10-fold higher than those in B6. Quantitative trait locus analysis of B6LEWESF2 offspring identified a major pPAI-1 regulatory locus on chromosome 5 from 136.1 to 137.6 Mb (logarithm of the odds score, 16.2). Significant pPAI-1 modifier loci on chromosomes 6 and 13 were also identified.Conclusion: Identification of pPAI-1 genomic regulatory elements provides insights into platelet/megakaryocyte-specific and cell type-specific gene expression. This information can be used to design more precise therapeutic targets for diseases where PAI-1 plays a role.
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页码：2917 / 2928
页数：12
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