Article

Minocycline protects against myocardial ischemia/reperfusion injury in rats by upregulating MCPIP1 to inhibit NF-κB activation

Authors: Quan Yi1, Fang-hui Tan1, Jia-an Tan1, Xiu-hui Chen1, Qing Xiao1, Ying-hua Liu1, Gui-ping Zhang1, Jian-dong Luo1,2
1 Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 510182, China
2 Guangzhou Institute of Cardiovascular Disease, Guangzhou Key Laboratory of Cardiovascular Disease, Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China
Correspondence to: Jian-dong Luo: jiandongluo@hotmail.com,
DOI: 10.1038/s41401-019-0214-z
Received: 5 November 2008
Accepted: 16 January 2019
Advance online: 21 February 2019

Abstract

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) dose-dependently 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-κB 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-κB activation and pro-inflammatory cytokine secretion.
Keywords: myocardial ischemia and reperfusion; H9c2 cardiomyocytes; oxygen glucose deprivation; minocycline; cytokine; NF-κB; monocyte chemotactic protein-induced protein-1

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