Role of MMP2 and MMP9 in TRPV4-induced lung injury

Abstract

Ca(2+) entry through transient receptor potential vanilloid 4 (TRPV4) results in swelling, blebbing, and detachment of the epithelium and capillary endothelium in the intact lung. Subsequently, increased permeability of the septal barrier and alveolar flooding ensue. In this study, we tested the hypothesis that TRPV4 activation provides a Ca(2+) source necessary for proteolytic disruption of cell-cell or cell-matrix adhesion by matrix metalloproteinases (MMPs) 2 and 9, thus increasing septal barrier permeability. In our study, C57BL/6 or TRPV4(-/-) mouse lungs were perfused with varying doses of the TRPV4 agonist GSK-1016790A (Sigma) and then prepared for Western blot. Lung injury, assessed by increases in lung wet-to-dry weight ratios and total protein levels in the bronchoalveolar lavage fluid, was increased in a dose-dependent fashion in TRPV4(+/+) but not TRPV4(-/-) lungs. In concert with lung injury, we detected increased active MMP2 and MMP9 isoforms, suggesting that TRPV4 can provide the Ca(2+) source necessary for increased MMP2/9 activation. Furthermore, tissue inhibitor of metalloproteinases (TIMP) 2 levels in the TRPV4-injured lungs were decreased, suggesting that TRPV4 activation increases the availability of these active MMPs. We then determined whether MMP2 and MMP9 mediate TRPV4-induced lung injury. Pharmacological blockade (SB-3CT, 1 μM; Sigma) of MMP2 and MMP9 resulted in protection against TRPV4-induced lung injury. We conclude that TRPV4 activation and the subsequent Ca(2+) transient initiates a rapid cascade of events leading to release and activation of the gelatinase MMPs, which then contribute to lung injury.

Dual contribution of TRPV4 antagonism in the regulatory effect of vasoinhibins on blood-retinal barrier permeability: diabetic milieu makes a difference

“…TRPV4 has been demonstrated to participate in both capacitative 24 and receptor-operated Ca 2+ entry 25–31 , and Ca 2+ entry through TRPV4 promotes the formation of Ca 2+ -calmodulin complexes, which can bind to TRPV4 enhancing channel activity 32,33 . Ca 2+ entry through TRPV4 has been also shown to increase lung endothelial cell permeability by disrupting cell-cell or cell-matrix adhesion 34,35 . A mechanism through which TRPV4 activation evokes the reorganization of actin cytoskeleton that associates with increased permeability may involve NO release 36,37 .…”

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…The TRPV4‐eNOS signaling achieves this feat by mediating the functional effect of TRPV4 channels, and by limiting the channel function through endothelial GC‐PKG signaling. While some pulmonary vascular disorders show reduced NO levels,10, 50, 51, 73 others show excessive TRPV4 channel activity 53, 54, 55, 74, 75. Thus, we propose that abnormalities in the NO‐PKG‐TRPV4 feedback mechanism may be involved in both types of pulmonary dysfunctions.…”

Collagenase IV plays an important role in regulating hair cycle by inducing VEGF, IGF-1, and TGF-β expression

“…SB-3CT is a selective inhibitor of MMP-2 and MMP-9, and is widely used to investigate the role of the enzymes 17,18. With this inhibitor, we provide the first evidence that collagenase IV plays an important role in hair cycle, which is mediated by VEGF, IGF-1, and TGF-β.…”

“…In addition, the increased expression of MMP-2 and MMP-9 has been demonstrated to be pathogenic in some diseases, such as cancer and lung injury 16,17…”