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Evidence to date suggests that β-arrestins act beyond their role as adapter proteins.Arginine vasopressin (AVP) may be a factor in inflammation and fibrosis in the pathogenesis of heart failure.In the present study we investigated the effect of AVP on inflammatory cytokine IL-6 production in murine hearts and the impact of β-arrestin 2-dependent signaling on AVP-induced IL-6 production.We found that administration of AVP (0.5 U/kg,iv) markedly increased the levels of IL-6 mRNA in rat hearts with the maximum level occurred at 6 h.In β-arrestin 2 KO mouse hearts,deletion of β-arrestin 2 decreased AVP-induced IL-6 mRNA expression.We then performed in vitro experiments in adult rat cardiac fibroblasts (ARCFs).We found that AVP (10-9-10-6 M) dosedependently increased the expression of IL-6 mRNA and protein,activation of NF-KB signaling and ERK1/2 phosphorylation,whereas knockdown of β-arrestin 2 blocked AVP-induced IL-6 increase,NF-KB activation and ERK1/2 phosphorylation.Pharmacological blockade of ERK1/2 using PD98059 diminished AVP-induced NF-KB activation and IL-6 production.The selective V1A receptor antagonist SR49059 effectively blocked AVP-induced NF-KB phosphorylation and activation as well as IL-6 expression in ARCFs.In AVP-treated mice,pre-injection of SR49059 (2 mg/kg,iv) abolished AVP-induced NF-KB activation and IL-6 production in hearts.The above results suggest that AVP induces IL-6 induction in murine hearts via the V1A receptor-mediated β-arrestin2/ERK1/2/NF-KB pathway,thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V1A/β-arrestin 2/ERK1/2/NF-KB signaling pathway.