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

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

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α(1)-adrenergic receptors (α(1)-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α(1)-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α(1)-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(1)-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.