Circulation research · 2026
PGK1 Drives Cardiac Hypertrophy by Regulating the Vimentin/PI3K/Akt Pathway.
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Zhu Xue-Xue, Zhang Ao-Yuan, Xu Gui-Wen, Li Rui, Gao Sheng-Qi, Ji Le-Ming, Li Yi-Fei, He Ting, Wei Min, Yang Le, Zhao Chen-Yang, Nürnberg Bernd, Beer-Hammer Sandra, Jin Yan, Li Xing, Han Zhi-Jun, Sun Hai-Jian
Аннотация
BACKGROUND: Pathological cardiac hypertrophy is a major risk factor for heart failure. PGK1 (phosphoglycerate kinase 1) plays an important role in cellular energy metabolism. However, the functions of PGK1 in cardiac hypertrophy remain largely unexplored.
METHODS: The expression and activity of PGK1, as well as its metabolite 3-phosphoglycerate, were examined in cardiac hypertrophy patients and mice subjected to transverse aortic constriction or Ang II (angiotensin II). Liquid chromatography-tandem mass spectrometry and co-immunoprecipitation analyses were used to identify the interacting proteins of PGK1. The potential effect of a PGK1 inhibitor CBR-470-1 was examined in a murine model of cardiac hypertrophy.
RESULTS: The activation and upregulation of PGK1 were observed in myocardium tissues from mice and patients with cardiac hypertrophy. Cardiomyocyte-specific PGK1-deficiency alleviated cardiac hypertrophy and dysfunction in mice. Conversely, cardiomyocyte-specific PGK1 overexpression or infusion of 3-phosphoglycerate exacerbated cardiac hypertrophy. Mechanistically, PGK1 functioned as a protein kinase to stimulate phosphorylation of vimentin (Ser83), followed by FAK (Focal Adhesion Kinase) /Src (sarcoma)-mediated phosphorylation of PI3K (Phosphoinositide 3-Kinase)/Akt (Protein Kinase B). The activated vimentin/PI3K/Akt signaling facilitated cardiomyocyte ferroptosis. Inhibition of PGK1 by CBR-470-1 prevented cardiac hypertrophy in cellular and animal models.
CONCLUSIONS: Our findings highlight a critical role for PGK1 in myocardial hypertrophy, with downstream activation of the vimentin/PI3K/Akt/ferroptosis pathway.
METHODS: The expression and activity of PGK1, as well as its metabolite 3-phosphoglycerate, were examined in cardiac hypertrophy patients and mice subjected to transverse aortic constriction or Ang II (angiotensin II). Liquid chromatography-tandem mass spectrometry and co-immunoprecipitation analyses were used to identify the interacting proteins of PGK1. The potential effect of a PGK1 inhibitor CBR-470-1 was examined in a murine model of cardiac hypertrophy.
RESULTS: The activation and upregulation of PGK1 were observed in myocardium tissues from mice and patients with cardiac hypertrophy. Cardiomyocyte-specific PGK1-deficiency alleviated cardiac hypertrophy and dysfunction in mice. Conversely, cardiomyocyte-specific PGK1 overexpression or infusion of 3-phosphoglycerate exacerbated cardiac hypertrophy. Mechanistically, PGK1 functioned as a protein kinase to stimulate phosphorylation of vimentin (Ser83), followed by FAK (Focal Adhesion Kinase) /Src (sarcoma)-mediated phosphorylation of PI3K (Phosphoinositide 3-Kinase)/Akt (Protein Kinase B). The activated vimentin/PI3K/Akt signaling facilitated cardiomyocyte ferroptosis. Inhibition of PGK1 by CBR-470-1 prevented cardiac hypertrophy in cellular and animal models.
CONCLUSIONS: Our findings highlight a critical role for PGK1 in myocardial hypertrophy, with downstream activation of the vimentin/PI3K/Akt/ferroptosis pathway.