摘要
The neonatal mammalian heart has a remarkable regenerative capacity,while the adult heart has difficulty to regenerate.A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth.In this study,we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation.Reversing metabolic reprogramming by carnitine palmitoyltransferase 1(CPT1)inhibition,using cardiac-specific Cpt1a and Cpt1b knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction.The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir,a CPT1 inhibitor.CPT1 inhibition,by decreasing poly(ADP-ribose)polymerase 1 expression,reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes,leading to decreased p38 MAPK phosphorylation,and stimulation of cardiomyocyte proliferation.Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation.CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.
基金
supported by grants from the National Key Research and Development Program of China(No.2022YFA1104500)
National Natural Science Foundation of China(No.81930008)
Natural Science Foundation of Sichuan Province(No.2023NSFSC1651,China)
the National Institutes of Health(No.DK134574 and No.DK119652,US).
