The Mechanism Underlying Metabolic Remodeling In Transverse Aortic Constriction(TAC)induced Failing Mouse Heart

Heart failure is a clinical syndrome showed cardiac systolic/diastolic dysfunction at the end stage of most cardiovascular disease.To review and explore the mechanism of HF pathogenesis and effective prevention measures has become a consensus of the basic and clinical researchers.Although the pathogenesis of HF has not been completely elucidated,more and more clinical observations have showed that energy deficiency may be an important pathogenesis of HF development.However,present studies on metabolic pattern of failure heart were still unclear,and the knowledge of biological events about metabolic remodeling was largely unk:nown.It is necessary to further explore metabolic remodeling and related events in failing process.This study focused on transverse aortic constriction(TAC)induced failing heart.After in vitro investigations such as echocardiography and electrocardiography,mice hearts were collected and total RNA and protein were extracted from left ventricular myocytes.Q-PCR and western blot were used for performing metabolic related genes levels and hypertrophic signals at different time points after TAC surgery and analyzing metabolic remodeling patterns in failing process.On this basis,several interesting events were deeply explored through histochemical and submicroscopical analysis.We found myocardial lipolysis and mitochondrial dynamics were tightly interacted with metabolic remodeling.The main results were as follows:①Metabolic remodeling in pressure overload induced failing heart was a complex event,performed downregulate transcriptional levels of glucose and fatty acid(FA)metabolic related genes,but FA metabolic related genes were decreased more significantly,forming a "FA shift to glucose" mode.② The upstream enzymes of glycolysis were more susceptible than downstream enzymes under pressure overload conditions,characterized by a higher degree of being inhibited.③As a hypertrophic signal,ERK activation was an early event in heart failure process.④ Sustained pressure overload stimuli induced myocardial lipids accumulation.Decreased transcription of lipolitic enzymes may have contribution to lipid droplets formation,and this process was influenced by ERK activation.⑤ Pressure overload also impaired transcriptional levels of electron transfer chain and mitochondrial related genes,and blocked mitochondrial dynamics through inhibiting Mfn2 exprssion.ERK signal also contributed to this process.Taken together,this study clarified a temporality from hypertrophic response to HF formation of mouse heart under sustained pressure overload stimuli,and investigated the "FA shift to glucose" metabolic remodeling pattern.Based on these,two aspects,intracellular lipolysis and mitochondrial dynamics,were deeply discussed to provide further understanding of metabolic remodeling.Our work gives new insight into HF therapy.