Objective: To explore the effect and mechanism of matrine (Mt.) on myocardial interstitial fibrosis induced by pressure overload. Methods: Pressure overloaded myocardial hypertrophy was produced by banding of aort...Objective: To explore the effect and mechanism of matrine (Mt.) on myocardial interstitial fibrosis induced by pressure overload. Methods: Pressure overloaded myocardial hypertrophy was produced by banding of aorta abdominalis in 67 male Sprague-Dawley rats weighing (200±15) g. The rats were assigned into one of the following groups: sham-operation control, operation control, operation group treated with matrine (15 mg/(kg·d)) and treated with carvedilol (Car.) (3.6 mg/(kg·d)) group. The rats were given drugs one day after operation. Five weeks after treatment, the left ventricular weight (LVW) was measured and the volume of myocardial cells was detected with Hematoxylin-Eosin (H-E) stain and Masson stain was used to assess the level of fibrosis of the myocardial matrix. Myocardial metalloproteinase activity was quantified with zymography, and survival rate was calculated. Results: Survival rate significantly decreased (P〈0.05), LVW/BW (body weight), MMP-2 (matrix metalloproteinase-2) activity (P〈0.05), size of cardiomyocytes and interstitial fibrosis obviously increased in the operation group compared with sham control group. Mr. and Car. treatment can significantly increase survival rate (P〈0.05), decrease LVW/BW (P〈0.05) and MMP-2 activity (P〈0.05), decrease size of cardiomyocytes and interstitial fibrosis compared with operation group. But there was difference compared with sham group. Conclusion: Matrine was shown to be able to prevent cardiac remodelling of bypertrophy cardium induced by pressure overload including myocardial hypertrophy and fibrosis which may be associated with the decrease in MMP-2 activity of heart.展开更多
Objective To investigate the effects of captopril on cardiac function and levels of energy-rich phosphates in pressure overload induced left ventricular hypertrophy rats. Methods One hundred and twenty SD rats were ra...Objective To investigate the effects of captopril on cardiac function and levels of energy-rich phosphates in pressure overload induced left ventricular hypertrophy rats. Methods One hundred and twenty SD rats were randomly divided into three groups: sham operation group (SH group, n=40),coarctation of abdominal aorta group (CAA group, n=40) and captopril treatment lmg~ 100g1 ~ d-1) group (CAP group, n=40). Left ventricular end-diastolic pressure (LVEDP), left venh-icular mass index (LVMI), levels of energy-rich phosphates and morphological changes of the myocardial mitochondria were compared at the 62 and 82 week after operation. Results At 62 week, in CAA group, LVMI and LVEDP were increased and _ dp/dtmax was decreased, while ATP and ADP were decreased and AMP was increased (P〈0.01). These changes were much obvious at 8th week (P〈0.01). Compared with those of CAA group, the parameters of heart function and energy-rich phosphates (ATP, ADP, AMP, TAN) in CAP group were improved significantly(P〈0.01) at the 6th and 8th week. In CAP group, the parameters of heart function and energy-rich phosphates (ADP, AMP, TAN) were much better at 8~ week than those at 6th week. The morphological change of mitochondria was less in CAP group than that in CAA group. Conclusion Captopril significantly improves myocardial energy metabolism in pressure overload rats and protects the function of myocardial mitochondria展开更多
To test the hypothesis that transient nonischemic stimulation of hypertrophy would render the heart resistant to subsequent ischemic stress,short-term transverse aortic constriction(TAC)was performed in mice and then ...To test the hypothesis that transient nonischemic stimulation of hypertrophy would render the heart resistant to subsequent ischemic stress,short-term transverse aortic constriction(TAC)was performed in mice and then withdrawn for several days by aortic debanding,followed by subsequent myocardial exposure to ischemia/reperfusion(I/R).Following I/R injury,the myocardial infarct size and apoptosis were markedly reduced,and contractile function was significantly improved in the TAC preconditioning group compared with the control group.Mechanistically,hypertrophic preconditioning remarkably alleviated I/R-induced oxidative stress,as evidenced by the increased reduced nicotinamide adenine dinucleotide phosphate(NADPH)/nicotinamide adenine dinucleotide phosphate(NADP)ratio,increase in the reduced glutathione(GSH)/oxidized glutathione(GSSH)ratio,and reduced mitochondrial reactive oxygen species(ROS)production.Moreover,TAC preconditioning inhibited caspase-3 activation and mitigated the mitochondrial impairment by deacetylating isocitrate dehydrogenase 2(IDH2)via a sirtuin 3(SIRT3)-dependent mechanism.In addition,the expression of a genetic deacetylation mimetic IDH2 mutant(IDH2 K413R)in cardiomyocytes,which increased IDH2 enzymatic activity and decreased mitochondrial ROS production,and ameliorated I/R injury,whereas the expression of a genetic acetylation mimetic(IDH2 K413Q)in cardiomyocytes abolished these protective effects of hypertrophic preconditioning.Furthermore,both the activity and expression of the SIRT3 protein were markedly increased in preconditioned mice exposed to I/R.Treatment with an adenovirus encoding SIRT3 partially emulated the actions of hypertrophic preconditioning,whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning.The present study identifies hypertrophic preconditioning as a novel endogenous self-defensive and cardioprotective strategy for cardiac I/R injury that induces IDH2 deacetylation through a SIRT3-dependent mechanism.A therapeutic strategy targeting IDH2 may be a promising treatment for cardiac ischemic injury.展开更多
文摘Objective: To explore the effect and mechanism of matrine (Mt.) on myocardial interstitial fibrosis induced by pressure overload. Methods: Pressure overloaded myocardial hypertrophy was produced by banding of aorta abdominalis in 67 male Sprague-Dawley rats weighing (200±15) g. The rats were assigned into one of the following groups: sham-operation control, operation control, operation group treated with matrine (15 mg/(kg·d)) and treated with carvedilol (Car.) (3.6 mg/(kg·d)) group. The rats were given drugs one day after operation. Five weeks after treatment, the left ventricular weight (LVW) was measured and the volume of myocardial cells was detected with Hematoxylin-Eosin (H-E) stain and Masson stain was used to assess the level of fibrosis of the myocardial matrix. Myocardial metalloproteinase activity was quantified with zymography, and survival rate was calculated. Results: Survival rate significantly decreased (P〈0.05), LVW/BW (body weight), MMP-2 (matrix metalloproteinase-2) activity (P〈0.05), size of cardiomyocytes and interstitial fibrosis obviously increased in the operation group compared with sham control group. Mr. and Car. treatment can significantly increase survival rate (P〈0.05), decrease LVW/BW (P〈0.05) and MMP-2 activity (P〈0.05), decrease size of cardiomyocytes and interstitial fibrosis compared with operation group. But there was difference compared with sham group. Conclusion: Matrine was shown to be able to prevent cardiac remodelling of bypertrophy cardium induced by pressure overload including myocardial hypertrophy and fibrosis which may be associated with the decrease in MMP-2 activity of heart.
基金Corresponding author: Dr. Cao Xuebin, MD, Department of Cardiology, 252 Hospital of Chinese PLA, Baoding 071000,Hebei Province,China Email: cxb252@yahoo.com.cn. This study was supported by the National Natural Science Foundation of China (30873398), Research Project of "Eleventh Five-year Plan" for Medical Science Development of PLA(2006MA064) and the Research Project of Hebei Province (06276012D- 114).
文摘Objective To investigate the effects of captopril on cardiac function and levels of energy-rich phosphates in pressure overload induced left ventricular hypertrophy rats. Methods One hundred and twenty SD rats were randomly divided into three groups: sham operation group (SH group, n=40),coarctation of abdominal aorta group (CAA group, n=40) and captopril treatment lmg~ 100g1 ~ d-1) group (CAP group, n=40). Left ventricular end-diastolic pressure (LVEDP), left venh-icular mass index (LVMI), levels of energy-rich phosphates and morphological changes of the myocardial mitochondria were compared at the 62 and 82 week after operation. Results At 62 week, in CAA group, LVMI and LVEDP were increased and _ dp/dtmax was decreased, while ATP and ADP were decreased and AMP was increased (P〈0.01). These changes were much obvious at 8th week (P〈0.01). Compared with those of CAA group, the parameters of heart function and energy-rich phosphates (ATP, ADP, AMP, TAN) in CAP group were improved significantly(P〈0.01) at the 6th and 8th week. In CAP group, the parameters of heart function and energy-rich phosphates (ADP, AMP, TAN) were much better at 8~ week than those at 6th week. The morphological change of mitochondria was less in CAP group than that in CAA group. Conclusion Captopril significantly improves myocardial energy metabolism in pressure overload rats and protects the function of myocardial mitochondria
基金supported by the National Natural Science Foundation of China(81870290,81521001,81800235,and 81800238)。
文摘To test the hypothesis that transient nonischemic stimulation of hypertrophy would render the heart resistant to subsequent ischemic stress,short-term transverse aortic constriction(TAC)was performed in mice and then withdrawn for several days by aortic debanding,followed by subsequent myocardial exposure to ischemia/reperfusion(I/R).Following I/R injury,the myocardial infarct size and apoptosis were markedly reduced,and contractile function was significantly improved in the TAC preconditioning group compared with the control group.Mechanistically,hypertrophic preconditioning remarkably alleviated I/R-induced oxidative stress,as evidenced by the increased reduced nicotinamide adenine dinucleotide phosphate(NADPH)/nicotinamide adenine dinucleotide phosphate(NADP)ratio,increase in the reduced glutathione(GSH)/oxidized glutathione(GSSH)ratio,and reduced mitochondrial reactive oxygen species(ROS)production.Moreover,TAC preconditioning inhibited caspase-3 activation and mitigated the mitochondrial impairment by deacetylating isocitrate dehydrogenase 2(IDH2)via a sirtuin 3(SIRT3)-dependent mechanism.In addition,the expression of a genetic deacetylation mimetic IDH2 mutant(IDH2 K413R)in cardiomyocytes,which increased IDH2 enzymatic activity and decreased mitochondrial ROS production,and ameliorated I/R injury,whereas the expression of a genetic acetylation mimetic(IDH2 K413Q)in cardiomyocytes abolished these protective effects of hypertrophic preconditioning.Furthermore,both the activity and expression of the SIRT3 protein were markedly increased in preconditioned mice exposed to I/R.Treatment with an adenovirus encoding SIRT3 partially emulated the actions of hypertrophic preconditioning,whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning.The present study identifies hypertrophic preconditioning as a novel endogenous self-defensive and cardioprotective strategy for cardiac I/R injury that induces IDH2 deacetylation through a SIRT3-dependent mechanism.A therapeutic strategy targeting IDH2 may be a promising treatment for cardiac ischemic injury.