Appropriate transient receptor potential vanilloid 4 (Trpv4) activation protects mice against lipopolysaccharide stress
Background: TRPV4 as a therapeutic target was used in endotoxemia research. However, conflicting results have been reported. It was reported that HC067047 as a TRPV4 inhibitor caused a reduction in LPS-induced mortality. Oppositely, TRPV4 inhibited with HC06047 could not attenuate LPS-induced symptoms and exaggerated pathology. The mechanism of conflict is still unknown. Material and methods: We assessed the pathological state in their experiments and further assessed the levels of TRPV4 expression with their respective treatment. Then the cell models with various levels of TRPV4 expression were used to explore the mechanism of conflicting results. The effect of TRPV4 expression on the apoptosis was observed under same LPS-dose stress. Meanwhile, F-actin contents were assessed with FITC-phalloidine staining. Results: Our experiments verified their results and further showed that TRPV4 expression differed between the two reports. We speculated that the different TRPV4 expression might have caused the conflicting results. Cell models of varying TRPV4 expression included normal TRPV4 expression and overexpression models. Results showed that TRPV4 overexpression significantly increased the apoptosis when compared with normal expression cells with the same lipopolysaccharide dose (P<0.05). HC067047 enhanced apoptosis in normal expression cells (P<0.05) and reduced apoptosis in overexpression cells (P<0.05). Research about the mechanism showed that HC06047 blocked TRPV4 signals, caused actin stress fiber accumulation, and induced apoptosis in normal expression cells. Oppositely, HC06047 inhibited relatively overactive TRPV4, attenuated excessive actin depolymerization, and reduced apoptosis ratios in overexpression cells. Conclusion: Underactive and/or overactive TRPV4 may be inhibitory to maintenance of cell function against lipopolysaccharide -induced stress.
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