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

Jizhong Wang, Jitao Liu, Fan Yang, Yinghao Sun, Jiaohua Chen, Jie Liu, Tucheng Sun, Ruixin Fan, Fang Pei, Songyuan Luo (), Jie Li () and Jianfang Luo ()
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Jizhong Wang: Guangdong Academy of Medical Sciences
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

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57011-5

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