Mice With Heart Failure And Experimental Links Between Related Signaling Pathways

Objective:To investigate the integration between cardiomyocyte signal pathy and the regulation of the hypertrophic response in dnMyD88 mice, a new model was generated to investigating myocardium hypertrophy and heart failure,through examining the diversification of some cardiomyocyte signals(MyD88,Akt,GSK3β,et al).Methods:All mice were grouped into transgenic(Tg)mice and wild-type(Wt)mice according to routine genotyping at the indicated age. Echocardiography was performed at the indicated age.Then hearts from all genotypes were collected to observing histopathological change. Cytoplasmic and nuclear protein was isolated to examining the diversification of MyD88/dnMyD88,Akt/pAkt,GSK3β/pGSK3β.Results:Compared with 8-week-old wild type mice,cardiac gross section of transgenic mice showed that the myocardial cell was dilated and it was progressed with older age.The re-expression of embryonic cardiac genes of ANF and BNP,as specific markers for pathologic cardiac hypertrophy and heart failure,was also observed in dnMyD88 mice by RT-PCR analysis.Compared with wild type mice,the data of echocardiography result of dnMyD88 mice indicated that left ventricular dimension increased,thickness of ventricular wall decreased and LV mass increased respectively.Echocardiographic index of LV function were significantly reduced in dnMyD88 group of mice.DnMyD88 group of mice showed progressive up-regulation of both endogenous MyD88 and dnMyD88 in myocardium.Akt signaling pathway(Akt,pAkt,GSK3β,pGSK3β)was progressively activated in myocardium of dnMyD88 mice.Conclusion:DnMyD88 transgenic mice show progressively decreasing of thickness of left ventricular wall and heart function,with dilating ventricular volume but no myocardium hypertrophy,which may ascribe to activating of Akt signaling pathway but which is worth further studying. Objective:To investigate new therapy of myocardium hypertrophy and heart failure,and to investigate the integrations between cardiomyocyte signal pathy and the regulation of the hypertrophic response in dnMyD88 mice through examining heart fabric and function between rapamycin group and vehicle group.Methods:DnMyD88 male mice were subgrouped into 8 groups according to genotyping,week age and recipient of rapamycin or vehicle. Echocardiography was performed after 14 days of intraperitoneal injection of rapamycin or vehicle at the dosage of 2mg/kg.Then cadiocyte mRNA and protein was isolated to examining the diversification of ANF,BNP by RT-PCR and MyD88/dnMyD88, Akt/pAkt,GSK3β/pGSK3βby western-blot.Results:Echocardiography index of heart function of Tg rapamycin group mice were improved than Tg control group.And index of myocardium fibrosis and heart function,ANF and BNP,were declined obviously in Tg rapamycin group.The expression levels of pAkt,pGSK3βand ratio of pAkt/Akt,pGSK3β/GSK3βin myocardium tissue were significantly decreased in rapamycin Tg group.Conclusion:Rapamycin,a mTOR inhibitor,can restrain the activation of Akt and the inactivation of GSK3βin myocardium of dnMyD88 transgenic mice.At the same time the heart function may be improved by rapamycin.The results prompted that the heart failure and myocardium fibrosis of dnMyD88 mice might be related to Akt and GSK3βsignal pathy.And rapamycin may be used for the therapy of heart failure. Objective:To probe the relationship between the cardiomyocyte signal pathy and the altering of mice's heart structure or function with aging, and to investigate the effect on aging heart function and signal pathy by rapamycin.Methods:C57BL/6J male mice were subgrouped into 6 groups in line with week age and recipient of rapamycin or not.Echocardiography was performed after 14 days of intraperitoneal injection of rapamycin or vehicle at the dosage of 2mg/kg.Then cadiocyte mRNA and protein was isolated to examining the diversification of ANF,BNP by RT-PCR and MyD88/dnMyD88,Akt/pAkt,GSK3β/pGSK3βby western-blot.Results:Compared with 8-week-old B6 mice,the data of echocardiography of B6 mice indicated that thickness of left ventricular wall increased obviously with aging.The indexes of heart function,FS, were found declined trend without statistical significance with aging.The re-expression of embryonic cardiac genes of ANF and BNP,as specific markers for cardiac hypertrophy and heart failure,was also observed in aged mice by RT-PCR analysis.The ratio of pAkt/Akt and pGSK3β/GSK3βwere also found inclined with aging.The thickness of ventricular wall and expression level of ANF and BNP of subgroups which receipted rapamycin were found declined significantly.And the ratio of pAkt/Akt and pGSK3β/GSK3βwere found restoration.Conclusion:Activation of Akt and GSK3βsignaling pathway might be regulators of myocardium hypertrophy and fibrosis in aging B6 mice. Through regulating the activating of Akt and GSK3βsignaling pathway, rapamycin may extenuate the myocardium hypertrophy and improve the left ventricular function.