The Anti-hypertrophy Effect Of STVNa And Its Protective Mechanism On Calcium Homeostasis

Cardiac hypertrophy is a chronic heart disease.Under the constant pathological,such as hypertension,neurohormone,cardiac hypertrophy will finally develop into heart failure.According to different pathological stimulus,clinical therapy often choose different anti-heart failure drugs to treat decompensated cardiac hypertrophy.Nevertheless,there is no effective drug with non-toxic side effects nowadays in the market.Therefore,it’s of importance to looking for an effective drug to protect and cure cardiac hypertrophy to further prevent occurrence of severe heart disease.Isosteviol is an diterpenoid compound obtained by hydrolysis of stevia acid.Isosteviol sodium(STVNa),a sodium salt of isosteviol,has lots of pharmacological activities,such as anti-cancer effect,anti-inflammation effect,antihypertension effect,neuron protection effect,hypolipidemic effect and hpyerglycemic effect.Preliminary study in our lab has shown that STVNa has obvious protection effect against cardiac ischemia reperfusion injury,while no documentary record has temporally shown any anti-hypertrophy effect of isosteviol.In this study,we have explore the possible pharmacological mechanism of STVNa on isoprenaline-induced cardiac hypertrophy.On in-vivo study,cardiac hypertrophy index and BNP mRNA expression are obviously decreased after applying 4mg/kg STVNa,as compared to hypertrophy group.By tissue slice observation,cross section area of cardiomyocytes have obviously decreased in STVNA group compared to hypertrophy group.By heart hemodynamic observation,STVNa can obviously restore left ventricular pressure and increase absolute value of Min dp/dt.While no obvious difference is observed in the value of Max dp/dt.Our result has shown that STVNa has protect effect against isoprenaline induced cardiac hypertrophy,and STVNa can improve cardiac diastolic function of hypertrophic heart without increasing cardiac loading.On study of cardiomyocytes contraction function,As compared to Positive inotropic agent ouabain and calcium sensitizer levosimendan,STVNa can obvious improve contraction of cardiomyocytes without affecting cytoplasmic calcium level.Our study finds that during the development of cardiac hypertrophy induced by isoprenaline,contraction function is improved at first and reduced afterwards.STVNa can obvious increase speed of contraction and rate of contraction in hypertrophic cardiomyocytes,indicating that STVNa can recovercontraction function of hypertrophic heart.Our results show that STVNa can strengthen contraction of cardiomyocyte meanwhile do not increase oxygen consumption.STVNa has more advantage as a potent protective agent for hypertrophy induced heart failure.Regulation of calcium homeostasis in cardiomyocytes is closely related to the development of pathological cardiac hypertrophy.Our study explores the possible mechanism of STVNa on calcium homeostasis in hypertrophic cardiomyocytes.After applying STVNa,QT duration and QTc duration are obviously decreased,indicating that STVNa can recover prolongation of action potential duration.Correspondingly,in vitro study shows that L-type calcium channel current in STVNa group is obviously decreased compared to hypertrophy group.In STVNa group,cytoplasmic calcium concentration and T50 are obviously decreased,F/F0 is obviously increased,as compared to hypertrophy group.The result indicates that STVNa can recover the calcium uptake function of cardiomyocytes.By calcium pool storage testing stimulated by caffeine,STVNa can obviously increase calcium pool storage in hypertrophic cardiomyocytes.Our results show that STVNa can maintain calcium homeostasis in hypertrophic heart,probably through a mechanism that preserve calcium uptake ralted protein.On in-vitro study,Our study has found that STVNa can decrease level of ROS and preserve mitochondrial membrane potential in hypertrophic cardiomyocytes,which shows that protect effect of STVNa on cardiac hypertrophy is related to ROS scavenging and mitochondrial membrane potential maintenance.Conclusion: STVNa has anti-hypertrophy effect.STVNa can improve contraction of pathological hypertrophic heart without increasing oxygen consumption,which is a promising drug for heart protection.The pharmacological effect of STVNa against cardiac hypertrophy may be related to maintaining calicum homeostasis.STVNa can reverse calcium regulation disorders provoked by pathological cardiac hypertrophy,especially for effectively regulating calcium uptake in hypertrophic heart.Upragualtion of PLB in myocardium may be involved.While,reduction of ROS and protection of mitochondrial membrane potential could also account for the anti-hypertrophic effect of STVNa.