Effect of A-۷۶۹۶۶۲, a direct AMPK activator, on Tlr-۴ expression and activity in mice heart tissue

Publish Year: 1395
نوع سند: مقاله ژورنالی
زبان: English
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شناسه ملی سند علمی:

JR_IJBMS-19-12_007

تاریخ نمایه سازی: 28 مهر 1400

Abstract:

Objective(s): TLR-۴ activates a number of inflammatory signaling pathways. Also, AMPK could be involved in anti-inflammatory signaling. The aim of this study was to identify whether stimulation of AMPK could inhibit LPS-induced Tlr-۴ gene expression in mice hearts. Materials and methods: Heart AMPK activity and/or Tlr-۴ expression was stimulated in different mice groups, using respectively IP injection of A-۷۶۹۶۶۲ (۱۰ mg/kg) and LPS (۲ mg/kg) or a combination of both agents. Moreover, compound-C (۲۰ mg/kg), as an AMPK antagonist, was intraperitoneally co-administrated with both A-۷۶۹۶۶۲ and LPS in another group to investigate the role of AMPK activity on Tlr-۴ regulation. After ۸ hr, in addition to peripheral neutrophil cell count, myocardial p-AMPK, p-ACC as well as MyD۸۸ protein contents and Tlr-۴ expression was assessed by Western blotting and real-time qRT-PCR, respectively. TNF-α and IL-۶ expression levels were also determined by ELISA. Results: LPS induced heart Tlr-۴ expression (P<۰.۰۰۱) associating with an increase in the myocardial MyD۸۸ protein content (P<۰.۰۰۱), elevation of heart TNF-α (P<۰.۰۱) and IL-۶ (P<۰.۰۵) concentrations, and rise in the peripheral neutrophil cell count (P<۰.۰۰۱). Administration of A-۷۶۹۶۶۲ decreased LPS-induced Tlr-۴ expression (P<۰.۰۱) and alleviated peripheral neutrophil cell count (P<۰.۰۱). The inhibitory effect of A-۷۶۹۶۶۲ on LPS-induced Tlr-۴ expression was reversed by antagonizing AMPK with compound-C (P<۰.۰۰۱) which reduced p-AMPK (P<۰.۰۵) and p-ACC (P<۰.۰۱) myocardial protein contents in the LPS+A-۷۶۹۶۶۲ group. Conclusion: This study demonstrated that activation of AMPK, by A-۷۶۹۶۶۲ agent, could inhibit Tlr-۴ expression and activity, suggesting a link between AMPK and Tlr-۴ in heart tissue.

Authors

Maryam Rameshrad

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

Nasrin Maleki-Dizaji

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

Hamid Soraya

Department of Pharmacology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran

Negisa Seyed Toutounchi

Student Research Committee, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

Abolfazl Barzegari

Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran

Alireza Garjani

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

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