Dandan Chen1, Zhe Li2, Peiqing Bao1, Miao Chen1, Miao Zhang1, Fangrong Yan3, Yitao Xu4, Caoyu Ji3, Xinyue Hu1, Daniel Sanchis5, Yubin Zhang6, Junmei Ye7. 1. State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. 2. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular research Institute, Wuhan University, Wuhan 430060, China; Hubei key Laboratory of Cardiology, Wuhan 430060, China. 3. Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing 210006, China. 4. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London W120NN, United Kingdom. 5. Institut de Recerca Biomedica de Lleida (IRBLLEIDA), Universitat de Lleida, Edifici Biomedicina-I. Av. Rovira Roure, 80, 25198 Lleida, Spain. Electronic address: daniel.sanchis@cmb.udl.cat. 6. State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. Electronic address: ybzhang@cpu.edu.cn. 7. State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. Electronic address: junmeiye@cpu.edu.cn.
Abstract
BACKGROUND: NF-E2-related factor 2 (Nrf2) is a transcription factor playing cytoprotective effects in various pathological processes including oxidative stress and cardiac hypertrophy. Despite being a potential therapeutic target to treat several cardiomyopathies, the signaling underlying Nrf2-dependent cardioprotective action remains largely uncharacterized. AIM: This study aimed to explore the signaling mediating the role of Nrf2 in the development of hypertensive cardiac pathogenesis by analyzing the response to Angiotensin II (Ang II) in the presence or absence of Nrf2 expression, both in vivo and in vitro. RESULTS: Our results indicated that Nrf2 deficiency exacerbated cardiac damage triggered by Ang II infusion. Mechanistically, our study shows that Ang II-triggered hypertrophy and inflammation is exacerbated in the absence of Nrf2 expression and points to the involvement of the IL-6/STAT3 signaling pathway in this event. Indeed, our results show that IL-6 abundance triggered by Ang II is increased in the absence of Nrf2 and demonstrate the requirement of IL-6 in STAT3 activation and cardiac inflammation induced by Ang II. CONCLUSION: Our results show that Nrf2 is important for the protection of the heart against Ang II-induced cardiac hypertrophy and inflammation by mechanisms involving the regulation of IL-6/STAT3-dependent signaling.
BACKGROUND:NF-E2-related factor 2 (Nrf2) is a transcription factor playing cytoprotective effects in various pathological processes including oxidative stress and cardiac hypertrophy. Despite being a potential therapeutic target to treat several cardiomyopathies, the signaling underlying Nrf2-dependent cardioprotective action remains largely uncharacterized. AIM: This study aimed to explore the signaling mediating the role of Nrf2 in the development of hypertensive cardiac pathogenesis by analyzing the response to Angiotensin II (Ang II) in the presence or absence of Nrf2 expression, both in vivo and in vitro. RESULTS: Our results indicated that Nrf2 deficiency exacerbated cardiac damage triggered by Ang II infusion. Mechanistically, our study shows that Ang II-triggered hypertrophy and inflammation is exacerbated in the absence of Nrf2 expression and points to the involvement of the IL-6/STAT3 signaling pathway in this event. Indeed, our results show that IL-6 abundance triggered by Ang II is increased in the absence of Nrf2 and demonstrate the requirement of IL-6 in STAT3 activation and cardiac inflammation induced by Ang II. CONCLUSION: Our results show that Nrf2 is important for the protection of the heart against Ang II-induced cardiac hypertrophy and inflammation by mechanisms involving the regulation of IL-6/STAT3-dependent signaling.
Authors: Beatriz Ferrer; Harshini Suresh; Abel Santamaria; João Batista Rocha; Aaron B Bowman; Michael Aschner Journal: Free Radic Biol Med Date: 2021-05-16 Impact factor: 8.101