Abstract
Sorting nexins (SNXs), the retromer-associated cargo binding proteins, have emerged as critical regulators of the trafficking of proteins involved in the pathogenesis of diverse diseases. However, studies of SNXs in the development of cardiovascular diseases, especially cardiac hypertrophy and heart failure, are lacking. Here, we ask whether SNX3, the simplest structured isoform in the SNXs family, may act as a key inducer of myocardial injury. An increased level of SNX3 was observed in failing hearts from human patients and mice. Cardiac-specific Snx3 knockout (Snx3-cKO) mice and Snx3 transgenic (Snx3-cTg) mice were generated to evaluate the role of Snx3 in myocardial hypertrophy, fibrosis, and heart function by morphology, echocardiography, histological staining, and hypertrophic biomarkers. We report that Snx3-cKO in mice significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy at 12 weeks. Conversely, Snx3-cTg mice were more susceptible to ISO-induced cardiac hypertrophy at 12 weeks and showed aggravated cardiac injury even heart failure at 24 weeks. Immunoprecipitation-based mass spectrometry, immunofluorescent staining, co-immunoprecipitation, localized surface plasmon resonance, and proximity ligation assay were performed to examine the direct interaction of SNX3-retromer with signal transducer and activator of transcription 3 (STAT3). We discovered that STAT3 was a new interacting partner of SNX3-retromer, and SNX3-retromer served as an essential platform for assembling gp130/JAK2/STAT3 complexes and subsequent phosphorylation of STAT3 by direct combination at EE. SNX3-retromer and STAT3 complexes were transiently imported into the nucleus after hypertrophic stimuli. The pharmacological inhibition or knockdown of STAT3 reversed SNX3 overexpression-induced myocardial injury. STAT3 overexpression blunts the beneficial function of SNX3 knockdown on hypertrophic cardiomyocytes. We show that SNX3-retromer promoted importin α3-mediated STAT3 nuclear trafficking and ultimately leading to cardiac injury. Taken together, our study reveals that SNX3 plays a key role in cardiac function and implicates SNX3 as a potential therapeutic target for cardiac hypertrophy and heart failure.
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Acknowledgements
We thank all patients who participated in this study for their cooperation. We also thank Jiantao Ye, Min Li, and Zhiping Liu for their excellent technical assistance.
Funding
This work was supported by grants from the National Natural Science Foundation of China (81803521, 81872860, 82003710, 82070464), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093), National Major Special Projects for the Creation and Manufacture of New Drugs (2019ZX09301104), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), Special Program for Applied Science and Technology of Guangdong Province (2015B020232009), Natural Science Foundation of Guangdong Province (2019A1515010273, 2021B1515020100), and Fundamental Research Funds for the Central Universities (19ykpy131).
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JL and PQL conceived the project. JL, ZKW, YHH, JJW, and XLZ designed and performed majority of the experiments and data analyses. SWX, YQH, and PQL provided scientific advice. DPS, PXW, ZML, and MYL performed several in vitro experiments. JL, ZKW, and PQL wrote the manuscript. JL, SWX, YQH, and DPS. critically revised this paper. All authors critically evaluated the manuscript.
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Lu, J., Xu, S., Huo, Y. et al. Sorting nexin 3 induces heart failure via promoting retromer-dependent nuclear trafficking of STAT3. Cell Death Differ 28, 2871–2887 (2021). https://doi.org/10.1038/s41418-021-00789-w
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DOI: https://doi.org/10.1038/s41418-021-00789-w
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