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Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and
Zhi Xu1, Francis J Castellino, Victoria A Ploplis
1The W. M. Keck Center for Transgene Research, 230 Raclin-Carmichael Hall, University of Notre Dame, Notre Dame, IN 46556, USA.
Insights
Plasminogen activator inhibitor-1 (PAI-1) deficiency leads to cardiac fibrosis in mice. Lack of PAI-1 causes inflammation and microvascular leakage, contributing to heart damage and dysfunction.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Molecular Medicine
Background:
- The role of plasminogen activator inhibitor-1 (PAI-1) in cardiac fibrosis is not fully understood.
- PAI-1 is involved in various fibrotic diseases, but its specific contribution to heart fibrosis is debated.
Purpose of the Study:
- To investigate the impact of PAI-1 deficiency on the development of cardiac fibrosis.
- To elucidate the mechanisms by which PAI-1 influences cardiac fibrogenesis.
Main Methods:
- Studied PAI-1 deficient (PAI-1(-/-)) mice to assess spontaneous cardiac fibrosis.
- Analyzed cardiac architecture, function, inflammation, microvascular permeability, and TGF-beta levels in PAI-1(-/-) and wild-type mice at different ages.
Main Results:
- PAI-1(-/-) mice developed spontaneous, age-dependent cardiac fibrosis with impaired cardiac function and architecture.
- Early PAI-1 deficiency in mice showed increased cardiac inflammation, microvascular permeability, and hemorrhage.
- Elevated levels of transforming growth factor-beta (TGF-beta) and proteases involved in tissue remodeling were observed in PAI-1(-/-) hearts.
Conclusions:
- PAI-1 deficiency promotes cardiac fibrosis through increased vascular permeability, inflammation, and extracellular matrix remodeling.
- PAI-1 appears to be cardioprotective by maintaining microvascular integrity.
- Loss of PAI-1 creates a pro-fibrotic environment in the heart.
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.
