α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation

Jun-zhou Xin1,2, Ji-min Wu2, Guo-min Hu2, Hui-jun Gu2,3, Ye-nan Feng2, Shuai-xing Wang2, Wen-wen Cong2,4, Ming-zhe Li2, Wen-li Xu2, Yao Song2, Han Xiao2, You-yi Zhang2, Li Wang1
1 The 3rd Department of Cardiology, The First Affiliated Hospital of the Medical College, Shihezi University, Shihezi 832008, China
2 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China
3 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China and 4Key Laboratory of Xinjiang Endemic
4 Ethnic Diseases, Department of Physiology, School of Medicine Shihezi University, Shihezi 832000, China
Correspondence to: You-yi Zhang:, Li Wang:,
DOI: 10.1038/s41401-019-0305-x
Received: 27 April 2019
Accepted: 29 August 2019
Advance online: 17 September 2019


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.
Keywords: α1-adrenergic receptor; cardiac inflammation; NOD-like receptor protein 3; inflammasome; caspase-1; interleukin-18; phenylephrine; prazosin

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