α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation

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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 α1-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, α1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.

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This work was supported by grants from the National Natural Science Foundation of China (81260028 to Li Wang, No. 81530009 to You-yi Zhang and No. 81670205 to Han Xiao), the Fund for Fostering Young Scholars of Peking University Health Science Center (No. BMU2017PY016 to Han Xiao) and the Open Foundation from Beijing Key Laboratory of Hypertension Research (No. 2017GXY-KFKT-05 to Han Xiao).

Author information

YYZ, HX, and LW conceived the project and designed the study. JZX, JMW, GMH, HJG, SXW, WWC, MZL, WLX, and YS performed the experiments. JZX, JMW, and YNF analyzed the data. JZX and JMW wrote the manuscript.

Correspondence to You-yi Zhang or Li Wang.

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The authors declare no competing interests.

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  • α1-adrenergic receptor
  • cardiac inflammation
  • NOD-like receptor protein 3
  • inflammasome
  • caspase-1
  • interleukin-18
  • phenylephrine
  • prazosin