Aims: Anemia of inflammation (AI), the second prevalent anemia, is associated with worse prognosis and increased mortality in numerous chronic diseases. We recently reported that the gasotransmitter hydrogen sulfide (H2S) suppressed the inflammatory activation of signal transducer and activator of transcription 3 (STAT3) and hepcidin, the critical mediators of AI. Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a novel inflammatory regulator and might be activated by H2S. In this study, we determined whether AMPK played a role in H2S-mediated anti-inflammatory response in AI and evaluated the therapeutic potential of AMPK against AI by pharmacological and clinical approaches.
Results: We showed that AMPK mediated the inhibition of STAT3, hepcidin, and AI by H2S during inflammation. Moreover, pharmacological and genetic activation of AMPK ameliorated hepcidin production, corrected iron dysregulation, and relieved hypoferremia and anemia in both acute and chronic inflammation models in mice. Mechanistic studies indicated that AMPK suppressed STAT3/hepcidin activation by promoting proteasome-mediated Janus kinase 2 (JAK2) degradation, which was dependent on the intact function of suppressor of cytokine signaling 1 (SOCS1) and increased interactions between SOCS1 and JAK2. Most importantly, the AMPK activator metformin was associated with decreased serum hepcidin content and anemia morbidity in Chinese type 2 diabetes mellitus patients.
Innovation: This is the first study to demonstrate the inhibition of inflammatory hepcidin and AI by AMPK-induced JAK2 degradation. Our work uncovered AMPK as a novel therapeutic target, and metformin as a potential therapy against AI.
Conclusion: The present work demonstrated that AMPK mediated the therapeutic effects of H2S and relieved AI by promoting SOCS1-mediated JAK2 degradation.
[1]Fudan Univ, Shanghai Key Lab Bioact Small Mol, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China.
[2]Macau Univ Sci & Technol, Sch Pharm, Dept Pharmacol, Macau, Peoples R China.
[3]Fudan Univ, Sch Med, Dept Oncol, Shanghai, Peoples R China.
[4]Fudan Univ, Huashan Hosp, Dept Endocrinol, Shanghai, Peoples R China.
[5]Shanghai Univ Tradit Chinese Med, Dept Clin Pharmacol, Shuguang Hosp, Shanghai, Peoples R China.
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