cGMP-mediated antioxidant signaling: a role for the c-Abl tyrosine kinase

Background Oxidant injury to the pulmonary endothelium contributes to acute lung injury. We have shown that activation of PKGI by cGMP increases protein levels of the antioxidant enzymes catalase and glutathione peroxidase-1 (GPx-1) and ameliorates oxidant injury in mouse lung endothelium [1]. Catalase and GPx-1 mRNA was not increased. The pathway downstream of PKGI that leads to increases in catalase and GPx-1 is unknown. The c-Abl tyrosine kinase has been reported to regulate catalase and GPx-1; fibroblasts deficient in c-Abl have increased levels of catalase and resist oxidant injury [2-4]. We hypothesized that 1) activation of PKGI would decrease c-Abl protein levels; and 2) inhibition of c-Abl with imatinib would increase antioxidant proteins and hydrogen peroxide (H2O2) degradation, attenuate H2O2-induced endothelial permeability, and decrease H2O2-induced cell death in mouse lung microvascular endothelial cells (MLVMEC).