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?1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.

ABSTRACT: Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by ?-adrenergic receptors (?-ARs). However, ?1-adrenergic receptors (?1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether ?1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of ?1-AR agonist phenylephrine (PE, 5 or 10?mg/kg, s.c.) with or without pretreatment with ?-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??M). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, ?1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.

SUBMITTER: Xin JZ

PROVIDER: S-EPMC7468364 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.

Xin Jun-Zhou JZ Wu Ji-Min JM Hu Guo-Min GM Gu Hui-Jun HJ Feng Ye-Nan YN Wang Shuai-Xing SX Cong Wen-Wen WW Li Ming-Zhe MZ Xu Wen-Li WL Song Yao Y Xiao Han H Zhang You-Yi YY Wang Li L

Acta pharmacologica Sinica 20190917 3

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α1-adrenergic receptors (α1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α ...[more]

PMID: 31530901

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Project description:The incidence of chronic liver disease is constantly increasing, owing to the obesity epidemic. However, the causes and mechanisms of inflammation-mediated liver damage remain poorly understood. Endoplasmic reticulum (ER) stress is an initiator of cell death and inflammatory mechanisms. Although obesity induces ER stress, the interplay between hepatic ER stress, NLRP3 inflammasome activation and hepatocyte death signaling has not yet been explored during the etiology of chronic liver diseases. Steatosis is a common disorder affecting obese patients; moreover, 25% of these patients develop steatohepatitis with an inherent risk for progression to hepatocarcinoma. Increased plasma LPS levels have been detected in the serum of patients with steatohepatitis. We hypothesized that, as a consequence of increased plasma LPS, ER stress could be induced and lead to NLRP3 inflammasome activation and hepatocyte death associated with steatohepatitis progression. In livers from obese mice, administration of LPS or tunicamycin results in IRE1? and PERK activation, leading to the overexpression of CHOP. This, in turn, activates the NLRP3 inflammasome, subsequently initiating hepatocyte pyroptosis (caspase-1, -11, interleukin-1? secretion) and apoptosis (caspase-3, BH3-only proteins). In contrast, the LPS challenge is blocked by the ER stress inhibitor TUDCA, resulting in: CHOP downregulation, reduced caspase-1, caspase-11, caspase-3 activities, lowered interleukin-1? secretion and rescue from cell death. The central role of CHOP in mediating the activation of proinflammatory caspases and cell death was characterized by performing knockdown experiments in primary mouse hepatocytes. Finally, the analysis of human steatohepatitis liver biopsies showed a correlation between the upregulation of inflammasome and ER stress markers, as well as liver injury. We demonstrate here that ER stress leads to hepatic NLRP3 inflammasome pyroptotic death, thus contributing as a novel mechanism of inflammation-mediated liver injury in chronic liver diseases. Inhibition of ER-dependent inflammasome activation and cell death pathways may represent a potential therapeutic approach in chronic liver diseases.

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?1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.

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α<sub>1</sub>-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation.

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