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Abstract Title:

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

Abstract Source:

Cardiovasc Res. 2019 Nov 27. Epub 2019 Nov 27. PMID: 31774487

Abstract Author(s):

Jingyuan Zhang, Xiaohui Lu, Mei Liu, Hanlu Fan, Han Zheng, Shanshan Zhang, Nafis Rahman, Sławomir Wołczyński, Adam Kretowski, Xiangdong Li

Article Affiliation:

Jingyuan Zhang

Abstract:

AIM: 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-1β (IL-1β) in patients with PAH. We showed that inflammasomes were activated in the PAH mice model and that melatonin attenuated IL-1β 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.

CONCLUSIONS: 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.

TRANSLATIONAL PERSPECTIVE: PAH is a pathophysiological syndrome associated with inflammation. Our study is the first to report a decrease in melatonin levels in patients with PAH, which provides insight to investigate melatonin or other circadian rhythm-related factors in the etiology of PAH. We demonstrate that melatonin improved PAH by inactivating inflammasome in the lungs of several mice models. The fact that melatonin is an endogenous hormone, may present an advantage for PAH therapy. Our data provide a theoretical basis for applying melatonin clinically, and inflammasomes may be a possible target of PAH treatment.

Study Type : Animal Study

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Sayer Ji
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