The Effect Of Neoandrographolide On Myocardial Ischemia-Reperfusion Injury

Background:Acute myocardial infarction(AMI)has become one of the leading causes of death worldwide and imposes an enormous burden on individuals and society.Partial or complete coronary artery occlusion depriving downstream tissues of oxygen and nutrients,early and rapid restoration of blood perfusion has been identified as the main treatment to prevent further tissue damage.However,the restoration of blood supply can independently induce myocardial injury,which is called myocardial ischemia-reperfusion(MI/R)injury.The pathophysiological mechanisms of MI/R include excessive generation of aerobic free radicals,calcium overload,mitochondrial damage,endoplasmic reticulum stress,and inflammatory response.Neoandrographolide(Neo)is one of the main diterpene lactones isolated from Koelreuteria paniculata leaves.It has been shown to have anti-inflammatory and antioxidant effects in a variety of diseases.However,the role of Neo in myocardial ischemia-reperfusion injury remains unclear.In the present study,we aimed to evaluate the cardioprotective effect of Neo on MI/R models and investigate its possible mechanism.Methods:We randomly and equally divided male C57BL/6 mice(2 months old)into SHAM group(SHAM),myocardial ischemia-reperfusion injury group(MI/R),and myocardial ischemia-reperfusion injury + Neoandrostenoside group(MI/R+ Neo)(n=11 per group).The left anterior descending coronary artery(LAD)was ligated for30 min and then released to establish the myocardial ischemia-reperfusion injury models.H9C2 cell line and primary neonatal rat cardiomyocytes were induced into the simulated I/R’s status and used to further validate the Neo’s role in vitro(n=5 per group).Infarct size,pathological change,cardiomyocyte apoptosis,proinflammatory cytokines,and indexes related to Bax/ Bcl-2 and NF-κB signaling pathways were analyzed in vivo or in vitro after pretreating with Neo.Results:Compared with the MI/R group,Neo treatment significantly suppressed infarct size,cardiac necrosis,and inflammatory cell infiltration,cardiomyocyte apoptosis,proinflammatory cytokines,Bax,Caspase 3,and p-NF-κB protein expressions,and the translocation of NF-κB subunit p65 from the cytoplasm to the nucleus in vivo or in vitro.Still,Bcl-2 and IκBa proteins were notably up-regulated after Neo pretreatment.Conclusion:Neo could ameliorate myocardial ischemia-reperfusion injury by its antiinflammatory and anti-apoptotic activities.It was closely associated with suppressing NF-κB signaling pathway activation and Caspase 3 protein overexpression in cardiomyocytes.