Hydrogen sulfide regulates vascular endoplasmic reticulum stress in apolipoprotein E knockout mice

Background Atherosclerosis is an important cardiovascular disease,becoming a major and increasing health problem in developed countries.However,the possible underlying mechanisms were not completely clear.In 2009,our research group first discovered that hydrogen sulfide(HS) as a novel gastrotransmitter played an important anti-atherosclerotic role.The study was designed to examine the regulatory effect of hydrogen sulfide(HS) on endoplasmic reticulum stress (ERS) in apolipoprotein E knockout(apoE) mice fed a Western type diet. Methods C57BL/6 mice and homozygous apoEmice were fed a Western type diet.C57BL/6 mice were injected intraperitonealy with normal saline(5 ml/kg per day) as control group.The apoEmice were treated with the same dose of normal saline as the apoEgroup,injected intraperitoneally with sodium hydrosulfide(NaHS,an HS donor,56μmol/kg per day) as the apoE+NaHS group and injected intraperitoneally with DL-propargylglycine(PPG,a cystathionine-γ-lyase inhibitor,50 mg/kg,per day) as the apoE+PPG group.After 10 weeks,the mice were sacrificed and the plasma lipids were detected.Sections of aortic root from these animals were examined for atherosclerotic lesions by HE and oil red O staining.The aortic ultrastructure and microstructure were analyzed with the help of light and electronic microscope.Glucose-regulated protein 78(GRP78),caspase-12,copper-andzinc-containing superoxide dismutase(Cu/ZnSOD) and Mn-containing superoxide dismutase(MnSOD) protein expression in aortic tissues were detected with immunohistochemistry.The level of intracellular reactive oxygen species(ROS) were measured by using a commercial assay kit. Results Compared with control mice,apoEmice showed increased plasma levels of total cholesterol(TC), triglyceride(TG) and low density lipoprotein(LDL),decreased high density lipoprotein(HDL),increased aortic plaque size,destroyed ultra-structure of aortic tissue,and increased expression of GRP78 and caspase-12 proteins.Compared with apoEmice,HS donor-treated apoEmice showed a decreased plasma LDL level,lessened plaque necrosis and attenuated aortic ultra-structural disorder.HS donor-treatment induced GRP78 expression but suppressed caspase-12 expression in aortic lesions.However,compared with apoEmice,PPG treated apoEmice showed enlarged plaque size,more severe ultrastructural disorder of the aortic tissue and reduced GRP78 staining in aortic lesions.The plasma lipids and the staining of caspase-12 in apoE+ PPG rats did not significantly differ from those in the apoEmice. Consistently,HS induced SOD expression,accompanied by a reduced level of ROS. Conclusion HS plays a regulatory role in aortic ERS and reduces atherosclerotic lesions in apoEmice fed with a Western type diet.