Journal
BLOOD
Volume 115, Issue 10, Pages 2038-2047Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-09-244962
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Funding
- NHLBI NIH HHS [P01 HL073750, HL073750, HL063682, R01 HL063682] Funding Source: Medline
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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. (Blood. 2010; 115: 2038-2047)
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