Atrial natriuretic peptide attenuated thrombin-induced pulmonary endothelial cell permeability via activation of Epac/Rap and PKA signaling cascades, which inhibited the Rho pathway.
Does ANP attenuate thrombin-induced pulmonary endothelial cell permeability in vitro?
ANP protects against agonist-induced pulmonary endothelial cell barrier dysfunction via inhibition of Rho signaling by Epac/Rap1-Rac and PKA signaling cascades.
Acute lung injury, sepsis, lung inflammation, and ventilator-induced lung injury are life-threatening conditions associated with lung vascular barrier dysfunction, which may lead to pulmonary edema. Increased levels of atrial natriuretic peptide (ANP) in lung circulation reported in these pathologies suggest its potential role in the modulation of lung injury. Besides well recognized physiological effects on vascular tone, plasma volume, and renal function, ANP may exhibit protective effects in models of lung vascular endothelial cell (EC) barrier dysfunction. However, the molecular mechanisms of ANP protective effects are not well understood. The recently described cAMP-dependent guanine nucleotide exchange factor (GEF) Epac activates small GTPase Rap1, which results in activation of small GTPase Rac-specific GEFs Tiam1 and Vav2 and Rac-mediated EC barrier protective responses. Our results show that ANP stimulated protein kinase A and the Epac/Rap1/Tiam/Vav/Rac cascade dramatically attenuated thrombin-induced pulmonary EC permeability and the disruption of EC monolayer integrity. Using pharmacological and molecular activation and inhibition of cAMP-and cGMP-dependent protein kinases (PKA and PKG), Epac, Rap1, Tiam1, Vav2, and Rac we linked ANP-mediated protective effects to the activation of Epac/Rap and PKA signaling cascades, which dramatically inhibited the Rho pathway of thrombin-induced EC hyper-permeability. These results suggest a novel mechanism of ANP protective effects against agonist-induced pulmonary EC barrier dysfunction via inhibition of Rho signaling by Epac/Rap1-Rac and PKA signaling cascades.
Birukova et al. (Thu,) conducted a other in Pulmonary endothelial barrier dysfunction. Atrial natriuretic peptide (ANP) was evaluated on Pulmonary endothelial cell permeability and disruption of EC monolayer integrity. Atrial natriuretic peptide attenuated thrombin-induced pulmonary endothelial cell permeability via activation of Epac/Rap and PKA signaling cascades, which inhibited the Rho pathway.