IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57011-5.html
   My bibliography  Save this article

GMRSP encoded by lncRNA H19 regulates metabolic reprogramming and alleviates aortic dissection

Author

Listed:
  • Jizhong Wang

    (Guangdong Academy of Medical Sciences
    Southern Medical University)

  • Jitao Liu

    (Southern Medical University)

  • Fan Yang

    (Southern Medical University)

  • Yinghao Sun

    (Southern Medical University)

  • Jiaohua Chen

    (Southern Medical University)

  • Jie Liu

    (Southern Medical University)

  • Tucheng Sun

    (Southern Medical University)

  • Ruixin Fan

    (Southern Medical University)

  • Fang Pei

    (Guangdong Academy of Medical Sciences)

  • Songyuan Luo

    (Southern Medical University)

  • Jie Li

    (Southern Medical University)

  • Jianfang Luo

    (Guangdong Academy of Medical Sciences
    Southern Medical University
    Guangdong Provincial People’s Hospital Nanhai Hospital)

Abstract

Metabolic disturbances are hallmarks of vascular smooth muscle cell (VSMC) phenotypic transitions, which play a critical role in the pathogenesis of aortic dissection (AD). In this study, we identify and characterize glucose metabolism regulatory protein (GMRSP), a protein encoded by lncRNA H19. Using VSMC-specific GMRSP induction in knock-in mice, adeno-associated virus-mediated GMRSP overexpression, and exosomal GMRSP delivery, we demonstrate significant improvements in AD and mitochondrial dysfunction. Mechanistically, GMRSP inhibits heterogeneous nuclear ribonucleoprotein (hnRNP) A2B1-mediated alternative splicing of pyruvate kinase M (PKM) pre-mRNA, leading to reduced PKM2 production and glycolysis. This reprogramming preserves the contractile phenotype of VSMCs and prevents their transition to a proliferative state. Importantly, pharmacological activation of PKM2 via TEPP-46 abrogates the protective effects of GMRSP in vivo and in vitro. Clinical relevance is shown by elevated plasma PKM2 levels in AD patients, which correlate with poor prognosis. Collectively, these findings indicate GMRSP as a key regulator of VSMC metabolism and phenotypic stability, highlighting its potential as a therapeutic target for AD.

Suggested Citation

  • Jizhong Wang & Jitao Liu & Fan Yang & Yinghao Sun & Jiaohua Chen & Jie Liu & Tucheng Sun & Ruixin Fan & Fang Pei & Songyuan Luo & Jie Li & Jianfang Luo, 2025. "GMRSP encoded by lncRNA H19 regulates metabolic reprogramming and alleviates aortic dissection," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57011-5
    DOI: 10.1038/s41467-025-57011-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57011-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-57011-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Charles J. David & Mo Chen & Marcela Assanah & Peter Canoll & James L. Manley, 2010. "HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer," Nature, Nature, vol. 463(7279), pages 364-368, January.
    2. Akinobu Matsumoto & Alessandra Pasut & Masaki Matsumoto & Riu Yamashita & Jacqueline Fung & Emanuele Monteleone & Alan Saghatelian & Keiichi I. Nakayama & John G. Clohessy & Pier Paolo Pandolfi, 2017. "mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide," Nature, Nature, vol. 541(7636), pages 228-232, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jian Han & Omer An & Xi Ren & Yangyang Song & Sze Jing Tang & Haoqing Shen & Xinyu Ke & Vanessa Hui En Ng & Daryl Jin Tai Tay & Hui Qing Tan & Dennis Kappei & Henry Yang & Leilei Chen, 2022. "Multilayered control of splicing regulatory networks by DAP3 leads to widespread alternative splicing changes in cancer," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Caroline E. Brun & Marie-Claude Sincennes & Alexander Y. T. Lin & Derek Hall & William Jarassier & Peter Feige & Fabien Le Grand & Michael A. Rudnicki, 2022. "GLI3 regulates muscle stem cell entry into GAlert and self-renewal," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Olga Boix & Marion Martinez & Santiago Vidal & Marta Giménez-Alejandre & Lluís Palenzuela & Laura Lorenzo-Sanz & Laura Quevedo & Olivier Moscoso & Jorge Ruiz-Orera & Pilar Ximénez-Embún & Nikaoly Ciri, 2022. "pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    4. Haipeng Fu & Tingyu Wang & Xiaohui Kong & Kun Yan & Yang Yang & Jingyi Cao & Yafei Yuan & Nan Wang & Kehkooi Kee & Zhi John Lu & Qiaoran Xi, 2022. "A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Shintaro Mise & Akinobu Matsumoto & Keisuke Shimada & Toshiaki Hosaka & Masatomo Takahashi & Kazuya Ichihara & Hideyuki Shimizu & Chisa Shiraishi & Daisuke Saito & Mikita Suyama & Tomoharu Yasuda & To, 2022. "Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Hannah E. Salapa & Patricia A. Thibault & Cole D. Libner & Yulian Ding & Joseph-Patrick W. E. Clarke & Connor Denomy & Catherine Hutchinson & Hashim M. Abidullah & S. Austin Hammond & Landon Pastushok, 2024. "hnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Roger Moreno-Justicia & Thibaux Van der Stede & Ben Stocks & Jenni Laitila & Robert A. Seaborne & Alexia Van de Loock & Eline Lievens & Diana Samodova & Leyre Marín-Arraiza & Oksana Dmytriyeva & Robin, 2025. "Human skeletal muscle fiber heterogeneity beyond myosin heavy chains," Nature Communications, Nature, vol. 16(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57011-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.