Minocycline is a tetracycline antibiotic and has been shown to play a protective role in cerebral and myocardial ischemia/ reperfusion (I/R).However,the underlying mechanism remains unclear.Herein,we investigated whether monocyte chemotactic protein-induced protein-1 (MCPIP1),a negative regulator of inflammation,was involved in the minocycline-induced cardioprotection in myocardial I/R in vivo and in vitro models.Myocardial ischemia was induced in rats by left anterior descending coronary artery occlusion for 1 h and followed by 48 h reperfusion.Minocycline was administered prior to ischemia (45 mg/kg,ip,BID,for 1 d) and over the course of reperfusion (22.5 mg/kg,ip,BID,for 2 d).Cardiac function and infarct sizes were assessed.Administration of minocycline significantly decreased the infarct size,alleviated myocardial cell damage,elevated left ventricle ejection fraction,and left ventricle fractional shortening following I/R injury along with significantly decreased pro-inflammatory cytokine IL-1β and monocyte chemoattractant protein-1 (MCP-1) levels in heart tissue.H9c2 cardiomyocytes were subjected to oxygen glucose deprivation (OGD) followed by reoxygenation (OGD/R).Pretreatment with minocycline (1-50 μmol/L) dosedependently increased the cell viability and inhibited OGD/R-induced expression of MCP-1 and IL-6.Furthermore,minocYcline dose-dependently inhibited nuclear translocation of NF-KB p65 in H9c2 cells subjected to OGD/R.In both the in vivo and in vitro models,minocycline significantly increased MCPIP1 protein expression;knockdown of MCPIP1 with siRNA in H9c2 cells abolished all the protective effects of.minocycline against OGD/R-induced injury.Our results demonstrate that minocycline alleviates.myocardial I/R injury via upregulating MCPIP1,then subsequently inhibiting NF-KB activation and pro-inflammatory cytokine secretion.