Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo

Authors

  • N. A. Gingles,

    1. Department of Medicine, University of California San Diego, San Diego, CA, USA
    2. Veterans Administration San Diego Healthcare System, San Diego, CA, USA
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  • H. Bai,

    1. Department of Medicine, University of California San Diego, San Diego, CA, USA
    2. Veterans Administration San Diego Healthcare System, San Diego, CA, USA
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  • L. A. Miles,

    1. Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA
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  • R. J. Parmer

    Corresponding author
    1. Department of Medicine, University of California San Diego, San Diego, CA, USA
    • Correspondence: Robert J. Parmer, Nephrology/Hypertension (9111-H), University of California, San Diego, 3350 La Jolla Village Drive, San Diego, California 92161, USA.

      Tel.: +1 858 552 8585, ext. 7356; fax: +1 858 552 7549.

      E-mail: rparmer@ucsd.edu

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  • Manuscript handled by: R. Medcalf
  • Final decision: D. Lane, 26 May 2013

Summary

Background

The mechanisms by which PAI-1 biosynthesis is altered during stress have not been fully elucidated. Studies suggest a major role for neuro-peptidergic modulation of the stress response by PACAP (pituitary adenylate cyclase-activating polypeptide), a member of the VIP/secretin/glucagon family.

Objective

We tested the hypothesis that PACAP regulates PAI-1 biosynthesis during stress in vivo.

Methods

PAI-1 gene expression was monitored by RT-PCR in adrenal glands harvested from C57BL/6J mice that were unstressed, or subjected to restraint stress for 2 h, or treated with PACAP.

Results

PAI-1 mRNA expression was markedly increased in adrenals from stressed mice. Restraint stress resulted in much smaller increments in adrenal tPA mRNA, suggesting that local adrenal tPA/PAI-1 biosynthetic balance is markedly altered by stress. The observed increases in PAI-1mRNA during stress were substantially blunted (55 ± 4%, < 0.001) by pretreatment with the specific PACAP receptor antagonist, PACAP6-38, compared with pretreatment with vehicle. Administration of the agonist PACAP1-38 alone resulted in a dose-dependent increase in tissue PAI-1 mRNA. PACAP1-38 administration also resulted in substantial increases in plasma PAI-1 antigen and active PAI-1 concentrations that were significantly greater in male mice than in female mice.

Conclusions

We conclude that adrenal PAI-1 mRNA expression is markedly increased by stress, and that the PACAP peptidergic signaling pathway plays a major role in mediating the stress-induced increase in PAI-1 biosynthesis.

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