Effect And Mechanism Of Controlled-release Angiogenic Agent On Cardiac Angiogenesis And Remodeling After Myocardial Infarction

ObjectiveMyocardial infarction(MI)continues to be a main cause of hospital admission and mortality worldwide.Despite their clinical importance,current treatments for MI still have several limitations.The local,intramyocardial injection of agents into the infarcted heart is an attractive option to initiate cardiac regeneration.Here,we evaluated the therapeutic effects and long-term retention of liraglutide loaded in poly(lactic co-glycolic acid)poly(ethylene glycol)(PLGA-PEG)(liraglutide-PLGA-PEG)and bioglass loaded in sodium alginate(BG-SA)on experimental MI.Materials and MethodsIn the first part,we loaded liraglutide in PLGA-PEG nanoparticles.Next,measure characterization of the PLGA-PEG nanoparticles and liraglutide release.The left anterior descending coronary artery(LAD)was identified and ligated.After the baseline and screening echocardiograms,the rats were randomly divided into different groups(liraglutide-PLGA-PEG;liraglutide-saline;PLGA-PEG;saline;sham groups).Finally,locally injected it into peri-infarct myocardial tissue and examined its suitability for inducing cardiac angiogenesis and eventually improving cardiac function.Cardiac function was evaluated via echocardiography.Infarct morphometry,angiogenesis and apoptosis were all analysed 4 weeks after agents injection.In the second part of the experiment,we loaded bioglass in sodium alginate.Next,for in vitro test,investigate the effects of the BG-SA on the vascularization of HUVECs(Human Umbilical Vein Endothelial Cells)and cytotoxicity on cardiomyoblast(H9C2)cells.The LAD was identified and ligated.After the baseline and screening echocardiograms,the rats were randomly divided into different groups(BG-SA;BG loaded in sodium saline;sodium alginate;saline;sham groups).Finally,locally injected it into peri-infarct myocardial tissue and examined its suitability for inducing cardiac angiogenesis and eventually improving cardiac function.Cardiac function was evaluated via echocardiography.Infarct morphometry,angiogenesis,angiogenic protein expression and apoptosis were all analysed 4 weeks after agents injection.ResultsIn the first part,liraglutide-PLGA-PEG have been shown to efficiently load liraglutide and release liraglutide in a sustained manner for up to four weeks.The released liraglutide retained bioactivity,as measured by its ability to activate liraglutide signaling pathways.More importantly,an intramyocardial injection of liraglutide-PLGA-PEG was sufficient to improve cardiac function(P < 0.05),attenuate the infarct size(P < 0.05),preserve wall thickness(P < 0.05),promote angiogenesis(P < 0.05)and prevent cardiomyocyte apoptosis(P < 0.05)without affecting glucose levels.In the second part of the experiment,in our in vitro results,the BG-SA hydrogel demonstrated good biocompatibility and showed increased vessel formation.Compared with the control treatment,BG-SA was sufficient to prompt angiogenesis(P < 0.05),up-regulate the expression of angiogenic proteins(P < 0.05),attenuate infarct size(P < 0.05),preserve wall thickness(P < 0.05)and eventually improve cardiac function(P < 0.05).ConclusionsOur results demonstrate the feasibility and effectiveness of the local,controlled,intramyocardial delivery of liraglutide-PLGA-PEG and BG-SA in myocardial regeneration via angiogenesis,suggesting that liraglutide-PLGA-PEG and BG-SA are potential therapeutic strategies for myocardial regeneration and thus represent an effective strategy for the MI treatment.