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?-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK1/2-NF-?B signal pathway in murine hearts.

ABSTRACT: Evidence to date suggests that ?-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 ?-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 ?-arrestin 2 KO mouse hearts, deletion of ?-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) dose-dependently increased the expression of IL-6 mRNA and protein, activation of NF-?B signaling and ERK1/2 phosphorylation, whereas knockdown of ?-arrestin 2 blocked AVP-induced IL-6 increase, NF-?B activation and ERK1/2 phosphorylation. Pharmacological blockade of ERK1/2 using PD98059 diminished AVP-induced NF-?B activation and IL-6 production. The selective V1A receptor antagonist SR49059 effectively blocked AVP-induced NF-?B 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-?B 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 ?-arrestin2/ERK1/2/NF-?B pathway, thus reveal a novel mechanism of myocardial inflammation in heart failure involving the V1A/?-arrestin 2/ERK1/2/NF-?B signaling pathway.

SUBMITTER: Sun SZ

PROVIDER: S-EPMC7470839 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK<sub>1/2</sub>-NF-κB signal pathway in murine hearts.

Sun Shu-Zhen SZ Cao Hong H Yao Na N Zhao Ling-Ling LL Zhu Xiao-Fang XF Ni Er-An EA Zhu Qi Q Zhu Wei-Zhong WZ

Acta pharmacologica Sinica 20190912 2

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 ...[more]

PMID: 31515529

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Project description:A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.

Dataset Information

?-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK1/2-NF-?B signal pathway in murine hearts.

Publications

β-Arrestin 2 mediates arginine vasopressin-induced IL-6 induction via the ERK<sub>1/2</sub>-NF-κB signal pathway in murine hearts.

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