Zn₂SiO₄ Bioceramic Material Alleviates Cardiac Remodeling After Myocardial Infarction

Acute Myocardial infarction（AMI）refers to the massive necrosis of myocardial cells caused by acute coronary artery occlusion,which is a common cardiovascular disease and a serious threat to human health.Cardiac dysfunction caused by cardiac remodeling is an important pathological feature of myocardial infarction.Objective:At present,although stem cell therapy,gene therapy and drug therapy can effectively inhibit cardiac remodeling after myocardial infarction,their disadvantages are obvious,such as the low cell retention rate of stem cell therapy,the risk of inducing arrhythmia in gene therapy and the poor efficacy of drug therapy.Therefore,there is an urgent need to develop a new treatment with good efficacy,high safety and easy clinical translation."Ion therapy"is an emerging method for the treatment of myocardial infarction.Extracts derived from calcium silicate have been shown to effectively alleviate the recovery of cardiac function after myocardial infarction,but due to its single ionic composition,there are certain defects in its efficacy.Therefore,this thesis aims to find a new composite ceramic material with better therapeutic effect on myocardial infarction and provide a new treatment method for myocardial infarction in clinical practice.Methods:This thesis mainly studied the therapeutic effect of silicate bioceramic materials on myocardial infarction through in vivo animal experiments and in vitro cell experiments:（1）In vitro,CCK-8 assay,real-time fluorescent quantitative PCR（q RT-PCR）and angiogenesis assay were used to evaluate the effect of Zn₂SiO₄extract on angiogenesis of mouse coronary artery endothelial cells（MCAECs）.The effects of Zn₂SiO₄leaching solution on apoptosis and mitochondrial dysfunction of H9C2 cells were evaluated by TUNEL,DHE,q RT-PCR and MMP assay.（2）Acute myocardial infarction model was established by left coronary artery ligation in vivo.Small animal ultrasound,TTC,Masson staining,CD31/α-SMA and TUNEL staining were used to evaluate the effects of tail vein injection of Zn₂SiO₄extract and myocardial injection of Zn₂SiO₄bioceramic-doped composite albumin hydrogel on cardiac function,infarct size,fibrosis,angiogenesis and apoptosis in mice.Results:（1）In vitro cell experiments showed that Zn₂SiO₄leaching liquor promoted the proliferation of MCAECs and the expression of angiogensis-related genes（VEGF,b FGF,Snail）.Zn₂SiO₄leaching solution could improve the viability of H9C2 cells,inhibit cardiomyocyte apoptosis,inhibit ROS production,protect mitochondria,down-regulate apoptosis-related genes Caspase3&9 and Bax,up-regulate anti-apoptotic genes Bcl-2 and mitochondrial Nrf2 and HO-1 expression.Zn²⁺and SiO₃^2-released from Zn₂SiO₄bioceramic materials exert a synergistic inhibitory effect on mitochondrial damage and ROS overproduction.The results of JC-1 staining and q RT-PCR analysis showed that SiO₃^2-,Zn²⁺,and SiO₃^2-and Zn²⁺could alleviate mitochondrial damage,in which Zn²⁺played a dominant role,but SiO₃^2-and Zn²⁺had the best effect together.Therefore,SiO₃^2-and Zn²⁺had a synergistic therapeutic effect.（2）In vivo animal experiments show that Both tail vein injection of Zn₂SiO₄extract and myocardial injection of Zn₂SiO₄bioceramics composite albumin hydrogel（Zn₂SiO₄/HSA）can effectively restore cardiac function,reduce myocardial infarction size,alleviate cardiac fibrosis,promote angiogenesis and reduce myocardial cell apoptosis in mice with myocardial infarction.Compared with local injection of Zn₂SiO₄/HSA composite hydrogel（local treatment）,systemic injection of Zn₂SiO₄extract（systemic treatment）has a better therapeutic effect on myocardial infarction.The therapeutic effect of Ca SiO₃/HSA and Zn₂SiO₄/HSA hydrogel on myocardial infarction in mice was compared by ultrasound detection,Masson staining and immunofluorescence staining.Zn₂SiO₄/HSA had better therapeutic effect on myocardial infarction in mice.The mechanism may be related to the synergistic regulation of SiO₃^2-and Zn²⁺in Zn₂SiO₄/HSA hydrogel.Conclusion:Zn₂SiO₄bioceramics can effectively inhibit pathological cardiac remodeling induced by myocardial infarction by promoting angiogenesis,scavenging ROS to protect myocardial mitochondria and inhibiting myocardial cell apoptosis.Moreover,Zn²⁺and SiO₃^2-have a synergistic effect on the treatment of myocardial infarction.