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Astragaloside Ⅳ (AsIV) is an active saponin extracted from Astragalus membranaceus,which has shown cardioprotective effects in a number of experimental animals.In this study we investigated the molecular mechanisms by which AsIV attenuated the myocardial ischemia reperfusion (MI/R)-induced injury in vitro and in vivo by focusing on calcium-sensing receptor (CaSR) and extracellular signal-regulated kinase 1/2 (ERK1/2).Rat neonatal cardiac myocytes were subjected to a hypoxia/reoxygenation (H/R) procedure in vitro,which significantly decreased the cell viability,increased lactate dehydrogenase (LDH) release,induced cardiomyocyte apoptosis,and increased [Ca2+]i.H/R also increased the expression of CaSR and decreased ERK1/2 phosphorylation levels in H/R-exposed myocytes.Pretreatment with AsIV (60 μmol/L) significantly improved the cell viability and decreased LDH release,attenuated myocyte apoptosis,decreased [Ca2+]i and CaSR expression,and increased the ERK1/2 phosphorylation levels.The protective effects of AslV against H/R injury were partially inhibited by co-treatment with a CaSR agonist,gadolinium chloride (GdCl3) or with a specific ERK1/2 inhibitor U0126.For in vivo studies,a rat MI/R model was established.Pre-administration of AslV (80 mg/kg every day,ig) significantly decreased the myocardium infarct size,creatine kinase-MB (CK-MB) production,serum cardiac troponin (cTnl) levels,and cardiomyocyte apoptosis in the rats with MI/R injury.The therapeutic effects of AslV were associated with the downregulation of CaSR expression and upregulation of ERK1/2 phosphorylation in myocardial tissues.In summary,astragaloside Ⅳ attenuates myocardial I/R injury via inhibition of CaSR/FRK1/2 and the related apoptotic signaling pathways.