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Lab Invest. 2014 Jun;94(6):633-44. doi: 10.1038/labinvest.2014.51. Epub 2014 Mar 31.

Vitronectin-binding PAI-1 protects against the development of cardiac fibrosis through interaction with fibroblasts.

Author information

1
1] Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA [2] Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
2
Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
4
1] Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA [2] Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
5
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Abstract

Plasminogen activator inhibitor-1 (PAI-1) promotes or abates fibrotic processes occurring in different organs. Binding of PAI-1 to vitronectin, an extracellular matrix component, may inhibit vitronectin-integrin complex-mediated cellular responses in pathophysiological conditions. To investigate the importance of plasmin suppression vs vitronectin-binding pathways of PAI-1 in cardiac fibrosis, we studied uninephrectomized mice fed a high salt diet and infused with angiotensin II (Ang II) together with different PAI-1 variants, including PAI-1AK (AK) that inhibits plasminogen activators but does not bind vitronectin, PAI-1RR (RR) that binds vitronectin but does not have protease inhibitory effects or control PAI-1 (CPAI), the control mutant that has similar molecular backbone and half-life as AK and RR while retaining all functions of native PAI-1. Compared with RR and CPAI, non-vitronectin-binding AK significantly increased expression of cardiac fibroblast marker, periostin (Ang+AK 8.40±3.55 vs Ang+RR 2.23±0.44 and Ang+CPAI 2.33±0.12% positive area, both P<0.05) and cardiac fibrosis (Ang+AK 1.79±0.26% vs Ang+RR 0.91±0.18% and Ang+CPAI 0.81±0.12% fibrotic area, both P<0.05), as well as Col1 mRNA (Ang+AK 12.81±1.84 vs Ang+RR 4.04±1.06 and Ang+CPAI 5.23±1.21 fold increase, both P<0.05). To elucidate mechanisms underlying the protective effects of vitronectin-binding PAI-1 against fibrosis, fibroblasts from normal adult human ventricles were stimulated with Ang and different PAI-1 variants. Protease inhibitory AK and CPAI increased supernatant fibronectin, while decreasing plasminogen activator/plasmin activities and matrix metalloproteinase. RR and CPAI variants significantly reduced fibroblast expression of integrin β3, vitronectin level in the supernatant and fibroblast adhesion to vitronectin compared with the non-vitronectin-binding AK. Further, RR and CPAI preserved apoptotic, decreased anti-apoptotic and proliferative activities in fibroblasts. Thus, PAI-1 promotes or protects against development of cardiac fibrosis differentially through the protease inhibitory pathway or through its binding to vitronectin.

PMID:
24687120
PMCID:
PMC4361016
DOI:
10.1038/labinvest.2014.51
[Indexed for MEDLINE]
Free PMC Article
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