title: Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture.
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.
authors.affiliation: The W. M. Keck Center for Transgene Research, 230 Raclin-Carmichael Hall, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000235:genetics; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism / Q000502:physiology*; D019610:Cytoprotection / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics / Q000503:physiopathology; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D017395:Plasminogen Activator Inhibitor 1; D003094:Collagen