Taxol prevents myocardial ischemia-reperfusion injury by inducing JNK-mediated HO-1 expression

Context: Ischemia/hypoxia and reperfusion impair mitochondria and produce a large amount of reactive oxygen species (ROS), which lead to mitochondrial and brain damage. Furthermore, heme oxygenase-1 (HO-1) as a cytoprotective gene protects cells against ROS-induced cell death in ischemia-reperfusion injury. Induction of HO-1 is involved in cytoprotective effects of taxol. Objective: We hypothesize that taxol protects cardiac myocytes possibly by preserving myocardial mitochondrial function and inducing HO-1 expression through the JNK pathway. Materials and methods: In this project, the perfused Langendorff hearts isolated from rats were randomly divided into five groups: control, ischemic, ischemic+taxol (0.1 mu M), ischemic+taxol (0.3 mu M), and ischemic+taxol (1 mu M). Briefly, following a 15min equilibration period, the control group was subject to normoxic perfusion for 120min; the ischemia group, normoxic reperfusion for 120min after 30min ischemia; the taxol groups, normoxic reperfusion for 120min after 30-min ischemia with taxol (0.1, 0.3, or 1 mu M). The microtubule disruption score, ROS levels, and the activity of mitochondrial electron transport chain complexes I and III were examined by using immunohistochemical methods and free radical detection kits. Western blot assay was employed to study the underlying mechanisms. Results: After Taxol treatment (0.1 mu M), the ischemic microtubule disruption score was reduced to 9.81.9%. The study revealed that 0.1, 0.3, and 1 mu M taxol reduced the level of ROS by 33, 46 and 51%, respectively (p<0.05). In additional, 0.3 and 1 mu M taxol dramatically increased the activity of mitochondrial electron transport chain complex I (99.11 +/- 2.59, 103.49 +/- 3.89) and mitochondrial electron transport chain complex III (877.82 +/- 12.08; 907.42 +/- 16.21; 914.73 +/- 19.39, *p<0.05). Additionally, phosphorylation levels of JNK1 were significantly increased in the taxol group. Furthermore, the expression level of HO-1 increased with taxol treatments, which could be inhibited by the specific inhibitor of JNK, SP600125. Discussion and conclusion: Taxol stabilized microtubules and effectively reduced ROS levels during ischemia. It also preserved the activity of mitochondrial complexes I and III. Interestingly, taxol induced the expression of HO-1 via the JNK pathway in cardiac myocytes.