间歇禁食通过调控FGF21分子改善压力超负荷型心力衰竭OACSTPCD

Objective To investigate the protective effect of intermittent fasting(IF)against the pressure overload-induced heart failure and its potential molecular mechanism.Methods The model of pressure overload-induced heart failure was established by transverse aortic constriction(TAC),and the mice were treated with ad libitum(ALb)or IF after operation.C57BL/6 mice were randomly divided into sham+ALb group,sham+IF group,TAC+ALb group and TAC+IF group.Wild-type(WT)and fibroblast growth factor 21(FGF21)knockout(Fgf21-/-)mice were randomly divided into WT+TAC+ALb group,WT+TAC+IF group,Fgf21-/-+TAC+ALb group and Fgf21-/-+TAC+IF group.After 8 weeks,the left ventricular ejection fraction(LVEF)and the left ventricular fraction shortening(LVFS)were detected by ultrasonography,the ratio of heart weight(HW)to body weight(BW)was calculated,serum BNP level was detected,the cardiac structure changes were observed by histopathological staining,the mitochondrial structure and function(ATP production,mitochondrial complex Ⅰ and Ⅴ activities)were observed and measured by transmission electron microscopy and molecular biology experiments,the myocardial reactive oxygen species(ROS)production was evaluated by DHE staining,the myocardial 4-hydroxyno-nenal(4-HNE)level was measured by ELISA kit,and the expressions of SIRT3 and SOD2 were determined by Western blot.Results Compared with sham+ALb group,LVEF and LVFS were decreased in TAC+ALb group(P<0.01),serum BNP level was increased(P<0.01),HW/BW value and the mean cross-sectional area of cardiomyocytes were increased(P<0.01),and the proportion of myocardial interstitial fibrosis was elevated(P<0.01).Compared with TAC+ALb group,LVEF and LVFS were increased in TAC+IF group(P<0.01),serum BNP level was decreased(P<0.01),HW/BW value and the mean cross-sectional area of cardiomyocytes were decreased(P<0.01),and the proportion of myocardial interstitial fibrosis was declined(P<0.01).There were no significant differences in all the above indexes between sham+ALb group and sham+IF group(P>0.05).Compared with WT+TAC+ALb group,LVEF and LVFS were increased in WT+TAC+IF group(P<0.01),serum BNP level was decreased(P<0.01),HW/BW value and the mean cross-sectional area of cardiomyocytes were decreased(P<0.01),the proportion of myocardial interstitial fibrosis was declined(P<0.01),ATP produc-tion and the mitochondrial complex Ⅰ and Ⅴ activities were improved(P<0.01),and ROS production and 4-HNE level were down-regulated(P<0.01).Compared with WT+TAC+ALb group,the expression and the deacetylation activity of SIRT3 were increased in WT+TAC+IF group(P<0.01).Compared with WT+TAC+IF group,LVEF and LVFS were decreased in Fgf21-/-+TAC+IF group(P<0.01),serum BNP level was increased(P<0.01),HW/BW value and the mean cross-sectional area of cardiomyocytes were increased(P<0.01),and the proportion of myocardial interstitial fibrosis was elevated(P<0.01),ATP production and mitochondrial complex Ⅰ and Ⅴ activities were decreased(P<0.01),and ROS production and 4-HNE level were significantly upregulated(P<0.01).Compared with WT+TAC+IF group,the expression and the deacetylation activity of SIRT3 were decreased in Fgf21-/-+TAC+IF group(P<0.01).There were no significant differences in all the above indexes between Fgf21-/-+TAC+ALb group and Fgf21-/-+TAC+IF group(P>0.05).Conclusion IF can improve the mitochondrial function and reduce the oxidative stress by regulating FGF21-SIRT3 signaling pathway,thus alleviating the myocardial remodeling and the cardiac dysfunction in mice with pressure overload-induced heart failure.