An inner abilitv of organism to protect itself can be triggered or motivated by pretreatment of brief intermittent ischemia or repetitive slight hypoxia and a POwerful defence and protection from severe injury of succ...An inner abilitv of organism to protect itself can be triggered or motivated by pretreatment of brief intermittent ischemia or repetitive slight hypoxia and a POwerful defence and protection from severe injury of successive ischemia or hypoxia can thus be achieved, The neuroprotective action exerted by preconditioning seems to be re1ated to up/down regulation of contents or activity of some known neuroactive chemicals and/or generation of some unknown antihypoxic/ischemic neuroactive chemicals or mechanisms in the brain.展开更多
The possible transduction mechanisms involved in ischemic preconditioning were reviewed briefly,Nitric oxide from the endothelium (and possible also from cardiac myocytes)by the action of bradykinin stimulates soluble...The possible transduction mechanisms involved in ischemic preconditioning were reviewed briefly,Nitric oxide from the endothelium (and possible also from cardiac myocytes)by the action of bradykinin stimulates soluble guanylate cyclase in the cytosol resulting in an elevation of cGMP. This may inhibit the inward slow Ca2+ current by stimulating a cGMP-dependent PDE’ to decrease cGMP levels. The translocation of PKC to membrane by DAG formation resulting from the activation of PLC phosphorylates a membrane protein that may link to the ATP-dependent K+ channel. The pathway may be stimulated by the adenosine A, receptors,muscarine acetylcholine M1, M3 and M5 receptors and a-adrenoceptors as well. The possible approaches for pharmacological exploitation are to minic the endogenous myocardial protective mediators by more selective and long acting analogues, to enhence these mediators by modulating their release, transport and uptake, to modulate myocardial cAMP and cGMP levels,to target guanine-nucleotide binding regulatory proteins and etc.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resistant to subsequent ischemic stress,short-term transverse aortic constriction(TAC)was performed in mice and then withdrawn for several days by aortic debanding,followed by subsequent myocardial exposure to ischemia/reperfusion(I/R).Following I/R injury,the myocardial infarct size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An inner abilitv of organism to protect itself can be triggered or motivated by pretreatment of brief intermittent ischemia or repetitive slight hypoxia and a POwerful defence and protection from severe injury of successive ischemia or hypoxia can thus be achieved, The neuroprotective action exerted by preconditioning seems to be re1ated to up/down regulation of contents or activity of some known neuroactive chemicals and/or generation of some unknown antihypoxic/ischemic neuroactive chemicals or mechanisms in the brain.
文摘The possible transduction mechanisms involved in ischemic preconditioning were reviewed briefly,Nitric oxide from the endothelium (and possible also from cardiac myocytes)by the action of bradykinin stimulates soluble guanylate cyclase in the cytosol resulting in an elevation of cGMP. This may inhibit the inward slow Ca2+ current by stimulating a cGMP-dependent PDE’ to decrease cGMP levels. The translocation of PKC to membrane by DAG formation resulting from the activation of PLC phosphorylates a membrane protein that may link to the ATP-dependent K+ channel. The pathway may be stimulated by the adenosine A, receptors,muscarine acetylcholine M1, M3 and M5 receptors and a-adrenoceptors as well. The possible approaches for pharmacological exploitation are to minic the endogenous myocardial protective mediators by more selective and long acting analogues, to enhence these mediators by modulating their release, transport and uptake, to modulate myocardial cAMP and cGMP levels,to target guanine-nucleotide binding regulatory proteins and etc.
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.
