Format

Send to:

Choose Destination
See comment in PubMed Commons below
Blood. 2010 Mar 11;115(10):2038-47. doi: 10.1182/blood-2009-09-244962. Epub 2009 Dec 15.

Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture.

Author information

  • 1The W. M. Keck Center for Transgene Research, 230 Raclin-Carmichael Hall, University of Notre Dame, Notre Dame, IN 46556, USA.

Abstract

Although the involvement of plasminogen activator inhibitor-1 (PAI-1) in fibrotic diseases is well documented, its role in cardiac fibrosis remains controversial. The goal of this study was to determine the effect of a PAI-1 deficiency (PAI-1(-/-)) on the spontaneous development of cardiac fibrosis. PAI-1(-/-) mice developed pervasive cardiac fibrosis spontaneously with aging, and these mice displayed progressively distorted cardiac architecture and markedly reduced cardiac function. To mechanistically elucidate the role of PAI-1 in cardiac fibrosis, 12-week-old mice were chosen to study the biologic events leading to fibrosis. Although fibrosis was not observed at this early age, PAI-1(-/-) hearts presented with enhanced inflammation, along with increased microvascular permeability and hemorrhage. A potent fibrogenic cytokine, transforming growth factor-beta (TGF-beta), was markedly enhanced in PAI-1(-/-) heart tissue. Furthermore, the expression levels of several relevant proteases associated with tissue remodeling were significantly enhanced in PAI-1(-/-) hearts. These results suggest that PAI-1 is cardioprotective, and functions in maintaining normal microvasculature integrity. Microvascular leakage in PAI-1(-/-) hearts may provoke inflammation, and predispose these mice to cardiac fibrosis. Therefore, a PAI-1 deficiency contributes to the development of cardiac fibrosis by increasing vascular permeability, exacerbating local inflammation, and increasing extracellular matrix remodeling, an environment conducive to accelerated fibrosis.

Comment in

PMID:
20009036
[PubMed - indexed for MEDLINE]
PMCID:
PMC2837335
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk