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Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice

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  • Xin Zhang

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Can Hu

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Zhen-Guo Ma

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Min Hu

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Xiao-Pin Yuan

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Yu-Pei Yuan

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Sha-Sha Wang

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Chun-Yan Kong

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Teng Teng

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

  • Qi-Zhu Tang

    (Hubei Key Laboratory of Metabolic and Chronic Diseases)

Abstract

The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.

Suggested Citation

  • Xin Zhang & Can Hu & Zhen-Guo Ma & Min Hu & Xiao-Pin Yuan & Yu-Pei Yuan & Sha-Sha Wang & Chun-Yan Kong & Teng Teng & Qi-Zhu Tang, 2023. "Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39159-0
    DOI: 10.1038/s41467-023-39159-0
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    References listed on IDEAS

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    1. Jin Yang & Konstantinos Savvatis & Jong Seok Kang & Peidong Fan & Hongyan Zhong & Karen Schwartz & Vivian Barry & Amanda Mikels-Vigdal & Serge Karpinski & Dmytro Kornyeyev & Joanne Adamkewicz & Xuhui , 2016. "Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
    2. Roselle Gélinas & Florence Mailleux & Justine Dontaine & Laurent Bultot & Bénédicte Demeulder & Audrey Ginion & Evangelos P. Daskalopoulos & Hrag Esfahani & Emilie Dubois-Deruy & Benjamin Lauzier & Ch, 2018. "AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    3. Diem Hong Tran & Herman I. May & Qinfeng Li & Xiang Luo & Jian Huang & Guangyu Zhang & Erica Niewold & Xiaoding Wang & Thomas G. Gillette & Yingfeng Deng & Zhao V. Wang, 2020. "Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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    Cited by:

    1. Xin Zhang & Yi-Peng Gao & Wen-Sheng Dong & Kang Li & Yu-Xin Hu & Yun-Jia Ye & Can Hu, 2024. "FNDC4 alleviates cardiac ischemia/reperfusion injury through facilitating HIF1α-dependent cardiomyocyte survival and angiogenesis in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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