Melatonin inhibits inflammasome-associated activation of endothelium and macrophages attenuating pulmonary arterial hypertension.

Aims Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome associated with pulmonary/systemic inflammation. Melatonin relieves PAH, but the molecular mode of action remains unclear. Here, we investigated the role of melatonin in normalizing vascular homeostasis. Methods and results Light-time mean serum melatonin concentration was lower in patients with PAH than in normal controls [11.06 +/- 3.44 (7.13-15.6) vs. 14.55 +/- 1.28 (8.0-19.4) pg/ml, which was negatively correlated with increased serum levels of interleukin-1 beta (IL-1 beta) in patients with PAH. We showed that inflammasomes were activated in the PAH mice model and that melatonin attenuated IL-1 beta secretion. On one hand, melatonin reduced the number of macrophages in lung by inhibiting the endothelial chemokines and adhesion factors. Moreover, use of Il1r(-/-) mice, Caspase1/11(-/-) mice, and melatonin-treated mice revealed that melatonin reduced hypoxia-induced vascular endothelial leakage in the Lung. On the other hand, we verified that melatonin reduced the formation of inflammasome multiprotein complexes by modulating calcium ions in macrophages using a live cell station, and melatonin decreased inositol triphosphate and increased cAMP. Furthermore, knockdown of melatonin membrane receptors blocked melatonin function, and a melatonin membrane receptors agonist inactivated inflammasomes in macrophages. Conclusion Melatonin attenuated inflammasome-associated vascular disorders by directly improving endothelial leakage and decreasing the formation of inflammasome multiprotein complexes in macrophages. Taken together, our data provide a theoretical basis for applying melatonin clinically, and inflammasomes may be a possible target of PAH treatment. [GRAPHICS] .