The Effect Of Mitochondrial Lactate Shuttle On The Development Of Myocardial Remodeling And Heart Failure Induced By Aortic Constriction In Mice

Objective:To determine the effect and mechanisms of monocarboxylate transporter 1(MCT1)-mediated mitochondrial lactate shuttle on ventricular remodeling and heart failure induced by transverse aortic constriction(TAC)in mice.Methods:1.An animal model of cardiac hypertrophy was created by TAC in male C57BL/6 mice.Cardiac dimensions and functions were evaluated by echocardiography after 2 weeks.4 weeks and 8 weeks following TAC,respectively.2.There were four groups:? Sham-operate group;?TAC 2 weeks(cardiac hypertrophy)group;?TAC 4 weeks(heart failure)group;?TAC 8 weeks(heart failure)group.3.Intracellular lactate and malondialdehyde(MDA)were measured by colorimetric.4.The proteins expression of cytochrome c,cleaved-caspase 9,cleaved-caspase 3 and MCT1 were detected by Western blot.5.Binding activity of NF-kB was detected by electrophoretic mobility shift assay(EMSA).6.Cardiomyocytes apoptosis were stained by the terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick-end labeling(TUNEL)technique using an in situ cell death detection kit,and visualized under a fluorescence microscope.Results:1.As echocardiography evaluation,the mice exhibited cardiac hypertrophy after TAC 2 weeks,heart failure after TAC 4 weeks,and severe heart failure after TAC 8 weeks.2.The concentrations of lactate and MDA were higher in heart failure and cardiac hypertrophy groups than the sham group.The concentrations of lactate and MD A were higher in heart failure groups than cardiac hypertrophy group.3.The proteins expression of cytochrome c,cleaved-caspase 9,cleaved-caspase 3 and MCT1 were higher in heart failure and cardiac hypertrophy groups than the sham group.The proteins expression of cytochrome c,cleaved-caspase 9,cleaved-caspase3 and MCT1 were higher in heart failure groups than cardiac hypertrophy group.4.NF-kB binding activity was higher in heart failure and cardiac hypertrophy groups than the sham group.NF-kB binding activity was higher in heart failure groups than cardiac hypertrophy group.5.Apoptotic rate was higher in heart failure and cardiac hypertrophy groups than the sham group.Apoptotic rate was higher in heart failure groups than cardiac hypertrophy group.Conclusions:MCT1-mediated mitochondrial lactate shuttle plays an important role in the development of myocardial remodeling and heart failure.The molecular mechanisms may through inducing oxidative stress,increasing NF-kB binding activity and activating mitochondrial control of apoptosis.