22 October 2019 : Animal Research
MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling PathwayYing-Jun Zhang123ACE, He Huang123AE*, Yu Liu123BE, Bin Kong123BD, Guangji Wang123BCD
Med Sci Monit 2019; 25:7898-7907
BACKGROUND: Myocardial apoptosis and inflammation play important roles in doxorubicin (DOX)-caused cardiotoxicity. Our prior studies have characterized the effects of myeloid differentiation protein 1(MD-1) in pathological cardiac remodeling and myocardial ischemia/reperfusion (I/R) injury, but its participations and potential molecular mechanisms in DOX-caused cardiotoxicity remain unknown.
MATERIAL AND METHODS: In the present study, MD-1 knockout mice were generated, and a single intraperitoneal injection of DOX (15 mg/kg) was performed to elicit DOX-induced cardiotoxicity. Cardiac function, histological change, mitochondrial structure, myocardial death, apoptosis, inflammation, and molecular alterations were measured systemically.
RESULTS: The results showed that the protein and mRNA levels of MD-1 were dramatically downregulated in DOX-treated cardiomyocytes. DOX insult markedly accelerated cardiac dysfunction and injury, followed by enhancements of apoptosis and inflammation, all of which were further aggravated in MD-1 knockout mice. Mechanistically, the TLR4/MAPKs/NF-κB pathways, which were over-activated in MD-1-deficient mice, were significantly increased in DOX-damaged cardiomyocytes. Moreover, the abolishment of TLR4 or NF-κB via a specific inhibitor exerted protective effects against the adverse effects of MD-1 loss on DOX-caused cardiotoxicity.
CONCLUSIONS: Collectively, these findings suggest that MD-1 is a novel target for the treatment of DOX-induced cardiotoxicity.
Keywords: Cardiotoxins, Doxorubicin, Antigens, Surface, cardiotoxicity, Membrane Glycoproteins, Mice, Knockout, Myocardial Reperfusion Injury, Myocardium, Myocytes, Cardiac, Toll-Like Receptor 4
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