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Downregulation of NUP93 aggravates hypoxia-induced death of cardiomyocytes in vitro through abnormal regulation of gene transcription

Acta Pharmacologica Sinica volume 44, pages 969–983 (2023)Cite this article

Abstract

Nuclear pore complex in the nuclear envelope plays an important role in controlling the transportation of RNAs, proteins and other macromolecules between the nucleus and cytoplasm. The relationship between abnormal expression of nucleoporins and cardiovascular diseases is unclear. In this study we investigated how myocardial infarction affected the expression and function of nucleoporins in cardiomyocytes. We separately knocked down 27 nucleoporins in rat primary myocardial cells. Among 27 nucleoporins, knockdown of Nup93, Nup210 and Nup214 markedly increased the expression of ANP and BNP, two molecular markers of cardiomyocyte function. We showed that Nup93 was significantly downregulated in hypoxic cardiomyocytes. Knockdown of Nup93 aggravated hypoxia-induced injury and cell death of cardiomyocytes, whereas overexpression of Nup93 led to the opposite effects. RNA-seq and bioinformatics analysis revealed that knockdown of Nup93 did not affect the overall transportation of mRNAs from the nucleus to the cytoplasm, but regulated the transcription of a large number of mRNAs in cardiomyocytes, which are mainly involved in oxidative phosphorylation and ribosome subunits. Most of the down-regulated genes by Nup93 knockdown overlapped with the genes whose promoters could be directly bound by Nup93. Among these genes, we demonstrated that Nup93 knockdown significantly down-regulated the expression of YAP1. Overexpression of YAP1 partially rescued the function of Nup93 knockdown and attenuated the effects of hypoxia on cell injury and cardiomyocyte death. We conclude that down-regulation of Nup93, at least partially, contributes to hypoxia-induced injury and cardiomyocyte death through abnormal interaction with the genome to dynamically regulate the transcription of YAP1 and other genes. These results reveal a new mechanism of Nup93 and might provide new therapeutic targets for the treatment of ischemia-induced heart failure.

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Fig. 1: Knockdown of nucleoporins resulted in abnormal expression of ANP and BNP in cardiomyocytes.
Fig. 2: Knockdown of Nup93 promoted hypoxia-induced cardiomyocyte injury and cell death.
Fig. 3: Overexpression of Nup93 suppressed hypoxia-induced cardiomyocyte injury and cell death.
Fig. 4: The function of Nup93 in cardiomyocytes was involved in chromatin binding related transcription.
Fig. 5: Knockdown of Nup93 markedly affected the transcription of mRNAs involved in oxidative phosphorylation and ribosome subunits.
Fig. 6: Transcriptional regulation by Nup93 occurs through direct interactions between Nup93 and chromosomes.
Fig. 7: Overexpression of YAP1 partially attenuated the effects of Nup93 knockdown and hypoxia on cell injury and death.
Fig. 8: Downregulation of YAP1α might contribute to the effects of hypoxia on cell injury and death.
Fig. 9: Overview of Nup93 on hypoxia-induced cell death.

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Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81800310, 82000283, 82070419, 82170275 and 82170233) and General Research Program in Medicine and Health of Zhejiang Province (2020369899).

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Author notes

  1. These authors contributed equally: Lei Pan, Xiao-wei Song, Jin-chao Song

Authors and Affiliations

  1. Department of Cardiology, Zhongshan Hospital of Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China

    Lei Pan & Jun-bo Ge

  2. Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Xiao-wei Song, Zhong-kai Wang, Song-qun Huang, Zhi-fu Guo, Song-hua Li & Xian-xian Zhao

  3. Department of Anesthesiology, Shidong Hospital of Shanghai, University of Shanghai for Science and Technology, Shanghai, 200433, China

    Jin-chao Song

  4. Department of Cardiology, No. 903 Hospital of Chinese People’s Liberation Army, Hangzhou, 310013, China

    Cheng-yong Shi

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  1. Lei Pan
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Contributions

JBG, XXZ, and XWS designed the study. LP, XWS, JCS, SHL, CYS, ZKW, and SQH conducted experiments. XWS, LP, and JCS wrote and drafted the manuscript. ZFG, XXZ, and JBG analyzed data. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Song-hua Li, Xian-xian Zhao or Jun-bo Ge.

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Pan, L., Song, Xw., Song, Jc. et al. Downregulation of NUP93 aggravates hypoxia-induced death of cardiomyocytes in vitro through abnormal regulation of gene transcription. Acta Pharmacol Sin 44, 969–983 (2023). https://doi.org/10.1038/s41401-022-01036-9

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