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Isorhynchophylline enhances Nrf2 and inhibits MAPK pathway in cardiac hypertrophy

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Abstract

Isorhynchophylline (IRN) is one of the major tetracyclic oxindole alkaloids found in Uncaria rhynchophylla. Studies have found that IRN has diverse biological activities including antioxidant, anti-apoptosis, and neuroprotection. However, little is known about the effect of IRN on the development of cardiac hypertrophy. In this study, we investigated the change of the cell surface area and nascent protein synthesis of cultured H9c2 cardiomyocytes on exposure to phenylephrine (PE) plus IRN, and thus confirmed that IRN ameliorated cardiomyocyte hypertrophy induced by PE in vitro. Meanwhile, it turns out that IRN is also effective in neonatal rat ventricular myocytes (NRVMs) stimulated with angiotensin II (AngII). We also showed that IRN prevented cardiac dysfunction in mice with pressure overload due to transverse aortic constriction (TAC) and attenuated cardiac hypertrophy and fibrosis. IRN treatment improved the cardiac function assessed by echocardiographic parameters fractional shortening (FS) as well as suppressed the cardiac hypertrophy phenotypes, such as the increasing of ventricular mass/body weight and myocyte cross-sectional area. RT-PCR analysis showed that IRN treatment also alleviated the expression of fetal genes of ANP, BNP, Myh7, and the correlated fibrosis genes including TGF-β1, collagen I, collagen III, and CTGF in vivo. Meanwhile, IRN had anti-oxidative effects on cardiac remodeling with suppressed 4-HNE and MDA. Western blot analysis showed that the Nrf2 nuclear translocation and MAPK pathway were involved in the potential mechanisms of IRN on cardiac hypertrophy inhibition. The results of our study provide further evidence that IRN is a promising drug for the treatment of cardiac hypertrophy.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81300459; No. 81300162), Natural Science Foundation of Shandong Province (No. ZR2016HM48). Project funded by China Postdoctoral Science Foundation (No. 2018T110694; No. 2017M610429; No. 2014M551921) and the International Postdoctoral Exchange Fellowship Program.

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Author notes

  1. Yongtao Zhang and Yuqian Cui contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The affiliated Hospital of Qingdao University, Qingdao, 266000, China

    Yongtao Zhang

  2. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, 250012, China

    Yongtao Zhang, Shuai Dai, Hao Wang, Weidong Qin, Hongna Yang, Han Liu, Jinfeng Yue, Dawei Wu, Jing Wang & Haipeng Guo

  3. Center for Reproductive Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China

    Yuqian Cui

  4. Department of Emergency, Qilu Hospital of Shandong University, Jinan, 250012, China

    Shuai Dai

  5. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Wei Deng

  6. Department of Critical Care Medicine, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, Jinan, 250012, People’s Republic of China

    Hao Wang, Weidong Qin, Hongna Yang, Han Liu, Jinfeng Yue, Dawei Wu, Jing Wang & Haipeng Guo

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  1. Yongtao Zhang
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Contributions

YT Zhang and YQ Cui contributed equally to this work. HP Guo, J Wang, and DW Wu conceived and designed research. YT Zhang, S Dai, H Wang, and WD Qin conducted all experiments. W Deng and HN Yang analyzed data. YT Zhang and YQ Cui wrote the manuscript. H Liu and JF Yue carried out data interpretation and discussion. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Jing Wang or Haipeng Guo.

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The authors declare that they have no conflicts of interest.

Ethical approval

All animal experiments were performed in accordance with the guidelines for the care and use of laboratory animals, published by the Ministry of the People’s Republic of China, and were approved by the Institutional Animal Care and Use Committee of Shandong University.

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Suppl Fig. 1

IRN attenuated protein synthesis and hypertrophy of NRVMs induced by AngII. a IRN alleviated the increased protein synthesis after treated by AngII. Cells were treated with or without IRN (25 μM) for 48 h. *P < 0.05 vs. corresponding control; #P < 0.05 vs. 1 μM AngII. b Real-time PCR results showing the mRNA levels of BNP and ANP genes after AngII treatment. *P < 0.05 vs. corresponding control; #P < 0.05 vs. 1 μM AngII. c The representative pictures of α-Actinin immunofluorescence staining. d The quantification of cardiomyocyte sizes after AngII and IRN treatment. All experiments were repeated 3 times. *P < 0.05 vs. corresponding control; #P < 0.05 vs. 1 μM AngII. (PDF 104 kb)

Suppl Fig. 2

Effect of IRN on Nrf2 and MAPKs signaling pathways in NRVMs stimulated with AngII. a, b Western blotting results of nuclear Nrf2 change in NRVMs. c–f Western blotting results of the total and phosphorylated protein levels of ERK1/2, P38 MAPK, and JNK. All experiments were repeated three times. *P < 0.05 vs. corresponding control; #P < 0.05 vs. AngII group. (PDF 163 kb)

Suppl Fig. 3

Nrf2 inhibition abolishes protective effect of IRN on cardiac hypertrophy in NRVMs. NRVMs transfected with (50 nM) Nrf2-siRNA and control-siRNA were treated or not with AngII 1 μM and IRN 25 μM for 48 h. a–c Effects of IRN, Nrf2-siRNA, and control-siRNA on the activation of Nrf2 and production of ROS in AngII-treated NRVMs. d Effects of IRN 25 μM, Nrf2-siRNA, and control-siRNA on the cardiomyocyte area in AngII-treated NRVMs. All experiments were repeated three times. *P < 0.05 vs. control group; #P < 0.05 vs. AngII + IRN group. (PDF 90 kb)

Suppl Fig. 4

Isorhynchophylline enhances Nrf2 and inhibits MAPK pathway in cardiac hypertrophy. A potential working model of IRN regulating oxidative stress, Nrf2 nuclear translocation and activation of MAPKs in cardiac hypertrophy. (PDF 63 kb)

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Zhang, Y., Cui, Y., Dai, S. et al. Isorhynchophylline enhances Nrf2 and inhibits MAPK pathway in cardiac hypertrophy. Naunyn-Schmiedeberg's Arch Pharmacol 393, 203–212 (2020). https://doi.org/10.1007/s00210-019-01716-0

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