Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 135, Issue -, Pages 134-148Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2019.08.002
Keywords
Dilated cardiomyopathy; Glycolytic metabolism; T-cell
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Funding
- National Natural Science Foundation of China [81670459, 81670373, 81771946, 81571749]
- National Key R&D Program of China [2016YFC1301100]
- Youth Innovation Science Research Foundation of the Second Affiliated Hospital of Harbin Medical University [kycx2018-01]
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Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4(+) T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CDC4(+) T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4(+) T-cell immunological status. Adoptive transfer of CD4(+) T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4(+) T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.
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