Protective effect of mitogen-activated protein kinase phosphatase 1 on tumor necrosis factor-α-mediated myocardial injury

Abstract

Objective To investigate the effect of mitogen-activated protein kinase phosphatase 1 (MKP1) on tumor necrosis factor-α (TNF-α)-induced myocardial injury. Methods Wild type (WT) and MKP1 transgene (MKP1) mice were randomly divided into 2 groups separately: WT group, WT+ TNF-α group and MKP1 group, MKP1+ TNF-α group. Mice in the WT+ TNF-α group and the MKP1+ TNF-α group were intraperitoneally injected with TNF-α at a dose of 6 mg/kg. Mice in the WT group and the MKP1 group were intraperitoneally injected with an equal amount of physiological saline. The MKP1 expression, myocardial injury marker level, myocardial mitochondrial division-associated protein 1 (Drp1), antioxidant and respiratory complex expression and mitochondrial apoptosis were measured, and t-test was used to analyze differences between groups. Results As compared with WT+ TNF-α group, MKP1+ TNF-α group showed down-regulation of Drp1 and Mff expression (Drp1: 1.80±0.20 vs. 1.00±0.30, t=-10.134, P<0.05; Mff: 2.80±0.20 vs. 1.10±0.30, t=-8.313, P<0.05), increased expression of glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPX) [GSH: (29±2) vs. (49±3) nmol/mg, t=12.127, P<0.05; SOD: (2.2±0.1) vs. (8.1±0.2) U/mg, t=10.301, P<0.05; GPX: (50±4) vs. (172±6) U/mg, t=11.136, P<0.05], increased expression of mitochondrial respiratory recombination Ⅲ and Ⅱ (complex Ⅲ: 1.00±0.20 vs. 2.20±0.12, t=10.715, P<0.05; complex Ⅱ: 1.10±0.09 vs. 1.90±0.08, t=8.312, P<0.05), down-regulation of Caspase-9 and bax expression (Caspase-9: 2.20±0.11 vs. 1.15±0.09, t=-5.210, P<0.05; bax: 2.30±0.12 vs. 1.42±0.09, t=-6.006, P<0.05). Conclusion The mechanism of TNF-α-induced myocardial injury involves excessive division of mitochondria, mitochondrial redox balance, destruction of energy metabolism and mitochondrial apoptosis. MKP1 overexpression can significantly inhibit the development of these adverse reactions, protect mitochondrial function and inhibit myocardial damage. Key words: Mitogen-activated protein kinase phosphatase 1; Tumor necrosis factor-α; Myocardial injury