alpha Ketoglutarate Promotes Cardiomyocyte Proliferation and Heart Regeneration after Myocardial Infarction

The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal (P) day 7. How to stimulate the adult cardiomyocyte to re-enter the cell cycle is still unsolved. Accumulating evidence suggests that cardiomyocyte proliferation depends on its metabolic state. Due to the tight connection between tricarboxylic acid cycle (TCA) metabolism and proliferation, we analyzed the TCA metabolites between P0.5 and P7 mouse hearts and found that alphaketoglutarate (alphaKG) ranked the first among the decreased metabolites. Intraperitoneal injection of exogenous alphaKG extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction (MI) by inducing adult cardiomyocyte proliferation, which was confirmed by increased endogenous alphaKG in Ogdh-siRNA-treated mice. Mechanistically, alphaKG activates Jmjd3, a histone lysine demethylase, regulating H3K27me3 levels and the transcription of cell cycle genes in cardiomyocytes. Our present study indicates that alphaKG promotes cardiomyocyte proliferation by Jmjd3-dependent demethylation and inactivation of H3K27me3, which is a potential therapeutic approach for treating MI and heart failure.