α 1 -AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α -adrenergic receptors (α -ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present s...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2020-03, Vol.41 (3), p.311
Main Authors: Xin, Jun-Zhou, Wu, Ji-Min, Hu, Guo-Min, Gu, Hui-Jun, Feng, Ye-Nan, Wang, Shuai-Xing, Cong, Wen-Wen, Li, Ming-Zhe, Xu, Wen-Li, Song, Yao, Xiao, Han, Zhang, You-Yi, Wang, Li
Format: Article
Language:English
Subjects:
Adrenergic alpha-1 Receptor Agonists - pharmacology
Animals
Dose-Response Relationship, Drug
Echocardiography
Heart - drug effects
Inflammasomes - drug effects
Inflammasomes - metabolism
Inflammation - chemically induced
Inflammation - metabolism
Inflammation - pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Structure
NLR Family, Pyrin Domain-Containing 3 Protein - deficiency
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Phenylephrine - pharmacology
Receptors, Adrenergic, alpha-1 - metabolism
Structure-Activity Relationship
Sympathetic Nervous System - drug effects
Sympathetic Nervous System - metabolism
Sympathetic Nervous System - pathology
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Summary:Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α -adrenergic receptors (α -ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α -AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α -AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 μM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3 mice compared with wild-type mice. In conclusion, α -AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.
ISSN:1745-7254