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Janus-faced signaling of cGMP in acute lung injury

The effect of increasing pulmonary endothelial cGMP concentration on endothelial function in acute lung injury appears to depend on 1) the presence of specific cGMP targets, 2) intracellular cGMP compartmentalization and 3) the timing of the increase in cGMP relative to the injury onset [14]. For example, we recently showed that pretreatment of pulmonary artery endothelial monolayers with 8pCPT-cGMP attenuated oxidant-induced barrier dysfunction by a cGMP-dependent kinase-1 (cGKI)-dependent mechanism [1, 2]. More recently, however, we found that the increase in endogenous lung cGMP resulting from increased NO production in a ventilator-induced lung injury (VILI) mouse model caused lung endothelial barrier dysfunction [4]. The injurious effect of sGC-derived cGMP in VILI was mediated by the simultaneous generation of phosphodiesterase 2A (PDE2A), which was stimulated by cGMP to hydrolyze cAMP. Interestingly, in the same model, pretreatment with BAY 41-2272 (1.5 μM) to stimulate sGC before injurious tidal volume ventilation attenuated VILI.

Recent evidence suggests that endothelial apoptosis may contribute to VILI [5] so we wondered if the protective effect of increasing lung endothelial cGMP before injury could be mediated by an anti-apoptotic effect of cGMP signalling. Mouse lung microvascular endothelial cells (MLMVEC) were isolated and purified by flow cytometry and shown to express cGK1 by Western blot and phosphorylation of VASP Ser235. A 6 hr pretreatment with 8pCPT-cGMP (50 μM), significantly attenuated H2O2-induced cell death assessed by flow cytometry (Annexin-, 7AAD-) and nuclear condensation. A similar protection was not observed in human pulmonary artery endothelial cells (HPAEC) which lack cGK1 expression in vitro. Restoration of cGK1 expression in HPAEC resulted in cGMP-mediated protection against oxidant cell death suggesting a cGK1-mediated effect. To determine if this protective effect was upstream of apoptotic signaling, MLMVEC from C57BL6 mice were treated with 8p-CPT-cGMP (50 uM) before exposure to increasing concentrations of H2O2. The extracellular H2O2 concentration ([H2O2]ext) was continuously measured with a H2O2 electrode. Compared with untreated cells, wildtype MLMVEC pre-treated with 8p-CPT-cGMP for 2 or 4 hrs (but not 30 min) significantly decreased the maximal Δ[H2O2]ext by 33 ± 11, 32 ± 10 and 25 ± 10% in cells exposed to 20, 50, and 100 μM H2O2, respectively (N = 8, P < 0.01). Consistent with this effect, 8pCPT-cGMP pretreatment attenuated H2O2-induced H2DCF fluorescence as well as p38MAPK and Akt phosphorylation suggesting that intracellular H2O2 concentration was also decreased. MLMVEC isolated from cGK1-/- mice failed to enhance H2O2 uptake suggesting cGK1-mediated signaling was responsible. An assessment of the major H2O2 degrading enzyme systems revealed a significant cGMP-mediated increase in catalase expression without an increase in catalase mRNA suggesting a post-translational effect.

We conclude that the effects of cGMP signalling on lung endothelial function in acute lung injury are complex and include both injurious and protective mechanisms depending on the specific downstream signalling pathways that are present. Activation of lung microvascular endothelial cell cGK1 by cGMP protects against oxidant-mediated cell death possibly through an increase in endothelial antioxidant function.


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Research supported by NIH/NHLBI, American Heart Association and the Flight Attendant Medical Research Institute. The cGK1 adenovirus and cGK1-/- mice were kindly provided by Drs. Ken Bloch and Alexander Pfeifer, respectively.

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Correspondence to David B Pearse.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Stephens, R.S., Rentsendorj, O., Schmidt, E.P. et al. Janus-faced signaling of cGMP in acute lung injury. BMC Pharmacol 9 (Suppl 1), S31 (2009).

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