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SMURF2 inhibition attenuates cardiac hypertrophy through blocking ubiquitination degradation of AXIN1

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac hypertrophy. SMURF2 (SMAD-specific E3 ubiquitin ligase 2) is an important member of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) family of HECT E3 ubiquitin ligases. In this study we investigated the regulatory role of SMURF2 in cardiac hypertrophy. Experiment models were established in mice by transverse aortic constriction (TAC) in vivo, as well as in neonatal rat cardiomyocytes (NRCMs) by treatment with angiotensin II (Ang II, 1 μM) in vitro. We showed that the expression levels of SMURF2 were significantly elevated in cardiac tissues from patients with cardiac hypertrophy and the two experiment models. In NRCMs, SMURF2 knockdown or treatment with a specific SMURF2 inhibitor heclin (8 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, evidenced by reduced mRNA levels of Anp, Bnp and β-Mhc as well as cell surface. Prophylactic or therapeutic administration of heclin (10 mg·kg–1·d–1, i.p., for 5 or 4 weeks) effectively suppressed TAC-induced cardiac hypertrophy, and rescued heart function. We demonstrated that SMURF2 interacted with AXIN1 and increased ubiquitination degradation of AXIN1 in myocardial tissues, activating the Wnt/β-catenin signaling pathway. Heclin inhibited the ubiquitination degradation of AXIN1 by SMURF2 to alleviate cardiac hypertrophy. In conclusion, upregulated SMURF2 leads to AXIN1 ubiquitination and degradation, thereby facilitating the progression of cardiac hypertrophy. SMURF2 inhibitor heclin may serve as a therapeutic strategy for the treatment of cardiac hypertrophy.

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Fig. 1: SMURF2 levels are increased in cardiac hypertrophy.
Fig. 2: Heclin alleviates Ang II-induced cardiomyocytes hypertrophy.
Fig. 3: Heclin prophylactic administration alleviates TAC-induced cardiac hypertrophy.
Fig. 4: Heclin therapeutic administration alleviates TAC-induced cardiac hypertrophy.
Fig. 5: Decreased AXIN1 levels are mediated by increased SMURF2 expression during cardiac hypertrophy.
Fig. 6: Heclin alleviates cardiac hypertrophy by inhibiting SMURF2-mediated AXIN1 ubiquitination degradation.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant No. 82121001, 92468301, 82030013, 82241211, 82222009, 82070278, 82470270, 82170404), the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China (grant No. 2023ZD0503100), and the Natural Science Foundation of Jiangsu Province (BK20240129).

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  1. These authors contributed equally: Ying Kang, Yan Zu, Qi-yao Fan

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Southeast University, Nanjing, 210009, China

    Ying Kang & Yong Ji

  2. Key Laboratory of Drug Targets and Translational Medicine for Cardio-cerebrovascular Diseases, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Medical Basic Research Innovation Center for Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Nanjing Medical University, Nanjing, 211166, China

    Yan Zu, Qi-yao Fan, Xia-meng Liu, Shi-qing Chen, Liu-liu Ruan, Xin Tang, Li-ping Xie & Yong Ji

  3. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Key Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, NHC Key Laboratory of Cell Transplantation, the Central Laboratory of the First Affiliated Hospital, Harbin Medical University, Harbin, 150081, China

    Yong Ji

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Contributions

YJ and LPX contribute to conceptualization; YK, YZ and XML contribute to methodology; YK, QYF and SQC implemented software; XT, YK, YZ and QYF validated; YJ, XT, YK, YZ and QYF conducted investigations; YJ, LPX, XT provided resources; YK, XML and LLR contributes to writing original draft; XT reviewed and edited the text; XT and YK contribute to visualization; YJ, LPX, XT contribute to supervision; YJ, LPX, XT contribute to funding acquisition.

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Correspondence to Xin Tang, Li-ping Xie or Yong Ji.

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Kang, Y., Zu, Y., Fan, Qy. et al. SMURF2 inhibition attenuates cardiac hypertrophy through blocking ubiquitination degradation of AXIN1. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01597-5

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