PGK1 Drives Cardiac Hypertrophy by Regulating the Vimentin/PI3K/Akt Pathway.

Abstract

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. 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. 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. Our findings highlight a critical role for PGK1 in myocardial hypertrophy, with downstream activation of the vimentin/PI3K/Akt/ferroptosis pathway.