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HTR2A promotes the development of cardiac hypertrophy by activating PI3K-PDK1-AKT-mTOR signaling

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Cell Stress and Chaperones Aims and scope

Abstract

5-Hydroxytryptamine receptor 2A (HTR2A) is a central regulator of fetal brain development and cognitive function in adults. However, the roles of HTR2A in the cardiovascular system are not fully understood. Here in this study, we explored the function of HTR2A in cardiac hypertrophy. Significantly, the expression levels of HTR2A mRNA and protein levels were upregulated in hypertrophic hearts of human patients. Besides, the expression of HTR2A was also upregulated in isoproterenol (ISO)-induced cardiac hypertrophy in the mouse. Next, the expression of HTR2A was knocked down with shRNA or overexpressed with adenovirus in neonatal rat cardiomyocytes, and ISO was used to induce cardiomyocyte hypertrophy. We showed that HTR2A knockdown repressed ISO-induced cardiomyocyte hypertrophy, which was demonstrated by decreased cardiomyocyte size and repressed expression of hypertrophic fetal genes (e.g., myosin heavy chain beta (β-Mhc), atrial natriuretic peptide (Anp), and brain natriuretic peptide (Bnp)). By contrast, HTR2A overexpression promoted cardiomyocyte hypertrophy. Of note, we observed that HTR2A promoted the activation (phosphorylation) of AKT-mTOR (mammalian target of rapamycin) signaling in cardiomyocytes, and repression of AKT-mTOR with perifosine or rapamycin blocked the effects of HTR2A on cardiomyocyte hypertrophy. Finally, we showed that HTR2A regulated AKT-mTOR signaling through activating the PI3K-PDK1 pathway, and inhibition of either PI3K or PDK1 blocked the roles of HTR2A in regulating AKT-mTOR signaling and cardiomyocyte hypertrophy. Altogether, these findings demonstrated that HTR2A activated PI3K-PDK1-AKT-mTOR signaling and promoted cardiac hypertrophy.

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Author contributions

Weinian Gao and Shuguang Zhao designed the study and wrote the manuscript. Weinian Gao performed most of the experiments with help from Na Guo. Ziying Chen and Wenli Zhang collected human samples. Fang Yan and Hongjuan Liao performed the animal study. Kui Chi isolated cardiomyocytes.

Funding

This study was supported by the Health Commission of Hebei Province (20190058).

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Authors and Affiliations

  1. Department of Cardiac Macrovascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China

    Weinian Gao, Shuguang Zhao, Ziying Chen, Wenli Zhang, Fang Yan & Hongjuan Liao

  2. Department of Cardiology, Shijiazhuang Traditional Chinese Medicine Hospital, Shijiazhuang, 050000, China

    Na Guo

  3. Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China

    Kui Chi

Authors
  1. Weinian Gao
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  2. Na Guo
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  3. Shuguang Zhao
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  4. Ziying Chen
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  5. Wenli Zhang
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  6. Fang Yan
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  7. Hongjuan Liao
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  8. Kui Chi
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Correspondence to Shuguang Zhao.

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The authors declare that they have no conflict of interest.

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All animal experiments were performed according to the terms of the Animal Committee of Hebei Medical University (#2018-M051).

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Ethics approval for the collection of human samples was obtained from the Committee of Hebei Medical University (#2018-P047).

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Gao, W., Guo, N., Zhao, S. et al. HTR2A promotes the development of cardiac hypertrophy by activating PI3K-PDK1-AKT-mTOR signaling. Cell Stress and Chaperones 25, 899–908 (2020). https://doi.org/10.1007/s12192-020-01124-x

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  • DOI: https://doi.org/10.1007/s12192-020-01124-x

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