Journal
CARDIOVASCULAR RESEARCH
Volume 119, Issue 6, Pages 1377-1389Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvad029
Keywords
Myocarditis; CD4(+) T cells; Th17 cells; Phosphoglycerate kinase 1; Glycolysis
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This study aims to elucidate the regulatory role of phosphoglycerate kinase 1 (PGK1) in CD4(+) T cells and experimental autoimmune myocarditis (EAM). The results showed that PGK1 expression was elevated in cardiac CD4(+) T and Th17 cells from myocarditis mice, and treatment with PGK1 inhibitor NG52 alleviated cardiac inflammation and fibrosis, improved contractile function, and regulated the proportion of T cell subgroups. Mechanistically, PGK1 may act as a key metabolic regulator of CD4(+) T cell differentiation and regulate Th17 cell differentiation by regulating glycolysis and the PDHK1-ROS axis.
Aims CD4(+) T cells are the major drivers of cardiac-specific autoimmunity in myocarditis, specifically Th1, Treg, and most significant Th17 cells. But the molecular mechanisms of their activation remain unclear. We aimed to elucidate the regulatory role of phosphoglycerate kinase 1 (PGK1) in CD4(+) T cells and experimental autoimmune myocarditis (EAM). Methods and results EAM was induced in BALB/c mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Single-cell sequencing analysis found that glycolysis and PGK1 expression were elevated in cardiac CD4(+) T and Th17 cells from myocarditis mice. Mice treated with PGK1 inhibitor NG52 showed less cardiac inflammation and fibrosis and better contractile function, as well as reduced cardiac infiltrating Th17 and Th1 cells and increased proportion of Treg. NG52 suppressed CD4(+) T cell activation and differentiation of mice and myocarditis patients in vitro. Mechanistically, inhibition of PGK1 suppressed glycolytic activity and decreased pyruvate dehydrogenase kinase 1 (PDHK1) phosphorylation, thereby increasing reactive oxygen species (ROS) production in mitochondria and thus preventing Th17 cell differentiation. Conclusion PGK1 may act as a key metabolic regulator of CD4(+) T cell differentiation and regulates Th17 cell differentiation by regulating glycolysis and the PDHK1-ROS axis. Targeting PGK1 might be a promising strategy for the treatment of myocarditis.
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