ABSTRACT
OBJECTIVE To investigate the effects of the peroxisome proliferator-activated receptors δ （PPARδ） agonist GW501516 on the injury of pulmonary artery endothelial cells （PAECs） induced by hypoxia and its mechanism. METHODS The cytotoxic effects of GW501516 were observed by detecting the relative survival rate of PAECs； the protein expression of PPARδ was determined by Western blot assay. The cellular model of PAECs injury was established under hypoxic conditions； using antioxidant N-acetylcysteine （NAC） as positive control， the effects of GW501516 on cell injury and reactive oxygen species （ROS） production were investigated by detecting cell apoptotic rate， cell viability， lactate dehydrogenase （LDH） activity and ROS levels. Using nuclear factor erythroid 2-related factor 2（Nrf2） activator dimethyl fumarate （DMF） as positive control， PAECs were incubated with GW501516 and/or Nrf2 inhibitor ML385 under hypoxic conditions； the mechanism of GW501516 on PAECs injury induced by hypoxia was investigated by detecting cell injury （cell apoptosis， cell viability， LDH activity）， the levels of superoxide dismutase （SOD）， glutathione peroxidase （GPx）， catalase （CAT）， malondialdehyde （MDA） and ROS， the expressions of Nrf2， heme oxygenase-1 （HO-1） and cleaved-caspase-3 （C-caspase-3） protein. RESULTS The results demonstrated that hypoxia inhibited the protein expression of PPARδ （P＜0.05）， while GW501516 promoted the protein expression of PPARδ in hypoxia- exposed PAECs without obvious cytotoxic effects. GW501516 inhibited the apoptosis of PAECs， improved cell viability， and reduced LDH activity and ROS levels. GW501516 could up-regulate the protein expression of HO-1 in PAECs and the levels of SOD， GPx and CAT， while down-regulated the levels of MDA and ROS by activating the Nrf2 pathway （P＜0.05）； but Nrf2 inhibitor ML385 could reverse the above effects of GW501516 （P＜0.05）. GW501516 exerted similar effects to Nrf2 activator DMF in down-regulating the expression of C-caspase-3 and inhibiting the injury of PAECs under conditions of hypoxia （P＜0.05）. Moreover， Nrf2 inhibitor ML385 reversed the 163.com inhibition effects of GW501516 on PAECs injury （P＜0.05）. CONCLUSIONS GW501516 can relieve the hypoxia-induced injury of PAECs via the inhibition of oxidative stress， the mechanism of which may be associated with activating Nrf2.
ABSTRACT
Objective To investigate the effect of preconditioning with sodium butyrate on myocardial I/R injury. Methods Anesthetized rats were treated with sodium butyrate (100 or 300 mg/kg, i.p.) 30 mins before ischemia, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. LDH, CK, TNF-α, IL-6, HMGB1, infarct size, MDA and SOD activity were measured. The infracted size was tested by TTC assay; The expression of HMGB1 was observed by western blot. Results After 4 h reperfusion, pretreatment of sodium butyrate (300 mg/kg) could significantly reduce the infarct size and the levels of LDH and CK (P<0.05)comparing to the control group; inhibit the increase of the MDA level and the decrease of the SOD level(P<0.05), also inhibit the expression of TNF-α, IL-6 and HMGB1 (all P < 0.05) induced by I/R. Conclusion Preconditioning of sodium butyrate can attenuate myocardial I/R injury by inhibiting inflammation response.