Troxerutin attenuates oxygen-glucose deprivation and reoxygenation-induced oxidative stress and inflammation by enhancing the PI3K/AKT/HIF-1a signaling pathway in H9C2 cardiomyocytes

Abstract

Myocardial ischemia-reperfusion (MI/R) injury is a complex pathological process that occurs when tissues are reperfused following a prolonged period of ischemia. Troxerutin has been reported to have cardioprotective functions. However, the underlying mechanism by which troxerutin protects against MI/R injury has not been fully elucidated. The aim of the present study was to explore whether troxerutin-mediated protection against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced H9C2 cell injury was associated with the inhibition of oxidative stress and the inflammatory response by regulating the PI3K/AKT/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. The results of the present study suggested that troxerutin pretreatment prevented the OGD/R- induced reduction in cell viability, and the increase in lactate dehydrogenase activity and apoptosis. Troxerutin reversed OGD/R- induced the inhibition of the PI3K/AKT/HIF-1α signaling pathway as demonstrated by the increased expression of PI3K and HIF-1α, and the increased ratio of phosphorylated AKT/AKT. LY294002, a selective PI3K inhibitor, inhibited the PI3K/AKT/HIF-1a signaling pathway and further attenuated the protective effect of troxerutin against OGD/R- induced H9C2 cell damage. Furthermore, small interfering (si)RNA- mediated knockdown of HIF-1a reduced troxerutin-induced protection against OGD/R injury. Troxerutin pretreatment alleviated OGD/R- induced oxidative stress, as demonstrated by the reduced generation of reactive oxygen species and malonaldehyde content, and the increased activities of superoxide dismutase and glutathione peroxidase, which were reduced by HIF-1a-siRNA . Troxerutin-induced decreases in the levels of interleukin (IL)-1β, IL- 6 and tumor necrosis factor-a in OGD/R conditions were also reduced by HIF-1α-siRNA . The results from the present study indicated that troxerutin aggravated OGD/R- induced H9C2 cell injury by inhibiting oxidative stress and the inflammatory response. The primary underlying protective mechanism of troxerutin was mediated by the activation of the PI3K/AKT/HIF-1α signaling pathway.