The Profile Of Myocardial Metabolism And The Cardioprotective Effect Of Mitochondrial Aldehyde Dehydrogenase 2 Activation During Cardiopulmonary Bypass

BackgroundIschemia-reperfusion injury by cross-clamping and declamping on aorta is currently thought to be inevitable in cardiac surgery with cardiplegia arrest.Researches focus on alleviating the injury and improving the prognosis in patients with cardiac surgery.The alteration of myocardium metabolism profile during ischemia-reperfusion has not been systematically investigated by metabolomics technology.Thus,we compared myocardial metabonomic profiling in rabbit with ischemia and ischemial-reperfusion to clarify the possible mechanism.MethodEighteen New Zealand white rabbits were randomly assigned into control group(C group,n=6),ischemia group(I group,n=6)and ischemia-reperfusion group(IR group,n=6).Another 12 rabbits were sacrificed as blood donors for groups I and IR.Cardiopulmonary bypass(CPB)was conducted by cannulation on subclavian artery and right atrium,and cardioplegia arrest was performed by cannulation into aortic root.Myocardium tissue was obtained after 120min ischemia and 120min reperfusion in I group and IR group,respectively.The control group was only conducted median sternotomy and CPB cannulation.The metabolic feature of myocardium was analyzed by a non-targeted metabolic profiling strategy based on gas chromatography-mass spectrometry.ResultsThe myocardial metabolic profiling was also slightly different between I and C groups(Q2Y= 0.357 for OPLS-DA models),and only thirteen definable metabolites varied significantly during ischemia comparing with C group(all VIP>1,and p<0.05),the metabolites were mainly involved in metabolism fatty acid,amino acid,and nucleotide.Whereas,myocardial metabolic profiling was significantly distinctive between IR and I groups(Q2Y= 0.714 for OPLS-DA models).Eighty-two definable metabolites varied significantly after ischemia-reperfusion comparing to ischemia group(all VIP>1,and p<0.05),which were mainly related to carbohydrate metabolism,amino acid metabolism,lipid synthesis,and nucleotide metabolism.Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed that metabolic pathways were mainly involved in increresed fatty acid synthesis,amino acid synthesis and urea cycle activation.The antioxidant system may also be relevant to the metabolic pathway.ConclusionIn present study,we identified metabolic imbalance,metabolic pathways,and biomarkers in a rabbit cardiopulmonary bypass model by applying metabolomics analysis,which may shed new lights on the further improvement of cardioprotection during cardiac surgury.BackgroundMitochondrial aldehyde dehydrogenase 2(ALDH2)attenuates cardiac damage caused by eliminating toxic aldehyde.However,the effect of ALDH2 activation on cardioprotection during cardiopulmonary bypass(CPB)remains unclear.The study investigated the cardioprotective effect of ALDH2 by applying Alda-1,a selective activator,that is applied in rabbit CPB model.MethodSectionl:Adult New Zealand white rabbits with age at 15-20 weeks and bodyweight at 2-3.5kg were used in our study.Twenty-one rabbits were randomly divided into three groups:cardiopulmonary bypass group(C group,conducted CPB without cardiac arrest,n=7),cardioplegic arrest group(CA group,n=7),cardioplegic arrest&Alda-1 group(CAA group,with both cardioplegic arrest and Alda-1 administration,n=7).Section2:Rabbits were randomly divided into four groups:cardioplegic arrest group(CA group,n=7),cardioplegic arrest&wortmannin group(CAW group,n=7),cardioplegic arrest&Alda-1 group(CAA group,n=7),cardioplegic arrest&Alda-1&wortmannin group(CAAW group,n=7).Another 35 rabbits were sacrificed as blood donors.Animals in the experimental groups were performed with cardiopulmonary bypass,after which the ascending aorta was clamped for 120min and then reperfusion for 120min.The rabbits in group C underwent normothermic CPB without cardiac arrest.The activity and content of ALDH2 and reactive aldehydes were determined at the end of reperfusion,as well as glutathione/oxidized glutathione ratios(GSH/GSSG),protein carbonyl,serum creatine kinase-MB(CK-MB),and AKT.TUNEL and LC3II/I assay were also evaluated for apoptosis and autophagy,respectively.Cardiac function was also assessed.ResultsIncreased ALDH2 activities and GSH/GSSG,and decreased levels of 4-hydroxynonenal and malondialdehyde were observed when Alda-1 was applied(all p<0.05).Increased ALDH2 activity attenuated the elevation of CK-MB and protein carbonyl.Alda-1 rescued IR-induced myocardial autophagy by the decreased LC3Ⅱ/Ⅰ in group CAA comparing with group CA.The dp/dtmax was improved by ALDH2 activation(pCA vs.CAA= 0.040).No significant difference was determined in TUNEL,LVEDP,LVESP,and dp/dtmin among the three groups.In the section 2 we found that p-AKT/AKT was elevated and LC3Ⅱ/Ⅰ were decreased between CA group and CAW group(p<0.05).The content of 4-HNE,p-AKT/AKT and LC3Ⅱ/Ⅰ were significantly different when CAA was compared with CA and CAAW groups,respectively.ConclusionThe results suggested that ALDH2 activation showed cardioprotection against I/R injury during CPB,which possibly attributed to the elimination of toxic aldehydes,alleviation of oxidative stress,I/R induced autophagy,and subsequent improvement of myocardial contractive function.In our rabbits CPB model,we found that ALDH2 could regulate down autophagy during repefsuion by elevating phosphorylation of AKT,but the molecular mechanisms should be futher analysis in the future.