Manuscript handled by: R. Medcalf
Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo
Article first published online: 12 SEP 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 9, pages 1707–1715, September 2013
How to Cite
Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo. J Thromb Haemost 2013; 11: 1707–15. DOI: 10.1111/jth.12333., , , .
Final decision: D. Lane, 26 May 2013
- Issue published online: 12 SEP 2013
- Article first published online: 12 SEP 2013
- Accepted manuscript online: 25 JUN 2013 09:20AM EST
- Manuscript Received: 6 NOV 2012
- National Institutes of Health. Grant Numbers: HL-50398, 0HL-081046, HL-45934
- Department of Veterans Affairs
- Pituitary adenylate cyclase-activating polypeptide;
- Plasminogen activator inhibitor-1;
- Sympathetic Nervous System;
- tissue plasminogen activator
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.
We tested the hypothesis that PACAP regulates PAI-1 biosynthesis during stress in vivo.
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.
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.
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.