Abstract： 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 (H2S) as a novel gastrotransmitter played an important anti-atherosclerotic role.The study was designed to examine the regulatory effect of hydrogen sulfide (H2S) on endoplasmic reticulum stress (ERS) in apolipoprotein E knockout (apoE(-/-)) mice fed a Western type diet.Methods C57BL/6 mice and homozygous apoE(-/-) mice were fed a Western type diet.C57BL/6 mice were injected intraperitoneally with normal saline (5 ml/kg per day) as control group.The apoE+ mice were treated with the same dose of normal saline as the apoE(-/-) group,injected intraperitoneally with sodium hydrosulfide (NaHS,an H2S donor,56μmol/kg per day) as the apoE(-/-)+NaHS group and injected intraperitoneally with DL-propargylglycine (PPG,a cystathionine-y-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,apoE(-/-) mice 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 apoE(-/-) mice,H2S donor-treated apoE(-/-) mice showed a decreased plasma LDL level,lessened plaque necrosis and attenuated aortic ultra-structural disorder.H2S donor-treatment induced GRP78 expression but suppressed caspase-12 expression in aortic lesions.However,compared with apoE/ mice,PPG treated apoE(-/-) mice 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 apoE(-/-)mice.Consistently,H2S induced SOD expression,accompanied by a reduced level of ROS.Conclusion H2S plays a regulatory role in aortic ERS and reduces atherosclerotic lesions in apoE(-/-) mice fed with a Western type diet.