Original Article
Peptidergic regulation of plasminogen activator inhibitor‐1 gene expression in vivo

https://doi.org/10.1111/jth.12333Get rights and content
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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%, P< 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.

Keywords

Pituitary adenylate cyclase‐activating polypeptide
Plasminogen activator inhibitor‐1
Stress
Physiological
Sympathetic Nervous System
tissue plasminogen activator

Cited by (0)

Manuscript handled by: R. Medcalf

Final decision: D. Lane, 26 May 2013