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

Amy E Siebert; Marisa A Brake; Stephanie C Verbeek; Alexander J Johnston; Andrew P Morgan; Audrey C Cleuren; Adrianna M Jurek; Caitlin D Schneider; Derrik M Germain; Fabia U Battistuzzi; Guojing Zhu; Darla R Miller; Jill M Johnsen; Fernando Pardo-Manuel de Villena; Matthew T Rondina; Randal J Westrick

doi:10.1016/j.jtha.2023.06.018

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

J Thromb Haemost. 2023 Oct;21(10):2917-2928. doi: 10.1016/j.jtha.2023.06.018. Epub 2023 Jun 25.

Authors

Amy E Siebert¹, Marisa A Brake¹, Stephanie C Verbeek¹, Alexander J Johnston¹, Andrew P Morgan², Audrey C Cleuren³, Adrianna M Jurek¹, Caitlin D Schneider¹, Derrik M Germain¹, Fabia U Battistuzzi⁴, Guojing Zhu³, Darla R Miller⁵, Jill M Johnsen⁶, Fernando Pardo-Manuel de Villena⁵, Matthew T Rondina⁷, Randal J Westrick⁸

Affiliations

¹ Department of Biological Sciences, Oakland University, Rochester, Michigan, USA.
² Department of Medicine, Duke University School of Medicine, Duke University, Durham, North Carolina, USA.
³ Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Biological Sciences, Oakland University, Rochester, Michigan, USA; Department of Bioengineering, Oakland University, Rochester, Michigan, USA; Centers for Data Science and Big Data Analytics and Biomedical Research, Oakland University, Rochester, Michigan, USA.
⁵ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁶ Department of Medicine, Institute for Stem Cell & Regenerative Medicine, and Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA.
⁷ Molecular Medicine Program, Departments of Internal Medicine and Pathology, the University of Utah, Salt Lake City, Utah, USA; The George E. Wahlen Department of Medical Affairs Medical Center, Salt Lake City, Utah, USA.
⁸ Department of Biological Sciences, Oakland University, Rochester, Michigan, USA; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Bioengineering, Oakland University, Rochester, Michigan, USA; Centers for Data Science and Big Data Analytics and Biomedical Research, Oakland University, Rochester, Michigan, USA; Eye Research Center and Department of Foundational Medical Studies, Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA. Electronic address: rjwestrick@oakland.edu.

PMID: 37364776
PMCID: PMC10826891 (available on 2024-10-01)
DOI: 10.1016/j.jtha.2023.06.018

Abstract

Background: Plasminogen activator inhibitor-1 (PAI-1, Serpine1) is an important circulating fibrinolysis inhibitor. PAI-1 exists in 2 pools, packaged within platelet α-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, B6LEWESF1. 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.

Keywords: blood platelets; fibrinolysis; gene expression regulation; megakaryocytes; quantitative trait loci; serpin E1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Blood Platelets* / metabolism
Fibrinolysis
Genomics
Humans
Mice
Mice, Inbred C57BL
Plasminogen Activator Inhibitor 1* / genetics
Plasminogen Activator Inhibitor 1* / metabolism
Quantitative Trait Loci

Substances

Plasminogen Activator Inhibitor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding