OSCP Overexpression Mediated By AAV9 Protected Myocardial Hypertrophy Induced By Pressure Overload

Objective: Test the effect of OSCP protein overexpression on cardiac remodeling in heart failure induced by TAC and its mechanism.Methods C57 mice were randomly divided into Sham+AAV9-c T NT-GFPgroup,Sham+A A V 9-c T N T-O S C P g r o u p,T A C + A A V 9-c T N T-G F P g r o u p a n d T A C +AAV9-c TNT-OSCP group.A mouse model of myocardial hypertrophy induced by aortic arch constriction(TAC)was constructed.Three days after surgery,AAV9-c TNT-OSCP /GFP virus was injected via tail vein.HE staining,masson staining and Sirius red staining were used to detect the degree of myocardial hypertrophy and fibrosis at the tissue level.Mitochondrial complex function was detected by OROBOROS Oxygraph-2k respiratory analyzer,and ATP level was detected by ATP hydrolysis kit.Results 1.Western bolt results showed that OSCP expression in myocardial tissue of TAC mice was lower than that of the normal control group(p<0.05).2.Four weeks after TAC surgery,echocardiography results showed that the cardiac function of mice after TAC surgery was decreased compared with Sham group,while HW/BW and HW/TL were increased compared with Sham group(P<0.05).Three days after TAC surgery,AAV9-c TNT-OSCP and AAV9-c TNT-GFP virus were injected into tail vein respectively for intervention.Four weeks after TAC surgery,Compared with TAC+ AAV9-c TNT-GFP group,cardiac systolic function indexes(LVEF and LVFS)of TAC+ AAV9-c TNT-OSCP group were increased(P<0.05).Meanwhile,HW/BW and HW/TL were decreased(P<0.05).3.After 4 weeks,paraffin sections of the heart tissues of mice were respectively stained with HE,masson and Sirius red.The results showed that the myocardial cell Cross-sectional area and fibrosis level in the TAC+ AAV9-c TNT-OSCP group were decreased compared with those in the TAC+ AAV9-c TNT-GFP group.Heart failure markers such as ANP also decreased.4.The function of mitochondrial complex was detected by OROBOROS Oxygraph-2k respiratory analyzer,and the results showed that Basal mitochondrial respiration capacities(Routine)? Maximal phosphorylating respiration capacity via convergent input through complexes I and II(OXPHOS CI?+?CII)and The maximal uncoupled respiratory capacity of the ETS(ETS CI?+?CII),as well as Inhibition of th e phosphorylation system by oligomycin(LEAK CI?+?CII)were increased in The TAC+ AAV9-c TNT-OSCP group compared with The TAC+ AAV9-c TNT-GFP group.5.Compared with the TAC+ AAV9-c TNT-GFP group,the mitochondrial ATP synthase activity of TAC+ AAV9-c TNT-OSCP group was enhanced.6.Compared with the TAC+ AAV9-c TNT-GFP group,the mitochondria of TAC+ AAV9-c TNT-OSCP group were more tolerant to calcium ions and inhibited the opening of m PTP channels.Conclusion: Mitochondrial dysfunction generally exist in the process of TAC induced myocardial hypertrophy and this process is accompanied by decreased expression of OSCP protein.AAV9-mediated OSCP overexpression in TAC induced myocardial hypertrophy mice model can attenuate mice myocardial hypertrophy after TAC surgery by improving mitochondrial function.