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H\n                      <jats:sub>2<\/jats:sub>\n                      S also lowers serum homocysteine in rats with mild hyperhomocysteinemia, but the pharmacological mechanism is unknown. The present study investigated the mechanism(s) involved.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      ApoE\u2010knockout mice were fed a Paigen diet and L\u2010methionine in drinking water for 16\u00a0weeks to create a mouse model of atherosclerosis with hyperhomocysteinemia. H\n                      <jats:sub>2<\/jats:sub>\n                      S donors (NaHS and GYY4137) were administered by intraperitoneal injection. We also assayed the H\n                      <jats:sub>2<\/jats:sub>\n                      S produced (by methylene blue assay and mito\u2010HS [H\n                      <jats:sub>2<\/jats:sub>\n                      S fluorescence probe]), cystathionine \u03b3 lyase (CSE) mRNA and protein expression, and CSE sulfhydration and nitrosylation and its activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      H\n                      <jats:sub>2<\/jats:sub>\n                      S donor treatment significantly lowered atherosclerotic plaque area, macrophage infiltration, and serum homocysteine level in the mouse model of atherosclerosis with co\u2010existing hyperhomocysteinemia. mRNA and protein levels of CSE, a key enzyme catalyzing homocysteine trans\u2010sulfuration, were down\u2010regulated with hyperhomocysteinemia, and CSE catalytic activity was inhibited. All these effects were reversed with H\n                      <jats:sub>2<\/jats:sub>\n                      S donor treatment. Hyperhomocysteinemia induced CSE nitrosylation, whereas H\n                      <jats:sub>2<\/jats:sub>\n                      S sulfhydrated CSE at the same cysteine residues. Nitrosylated CSE decreased and sulfhydrated CSE increased its catalytic and binding activities towards L\u2010homocysteine. Mutation of C252, C255, C307, and C310 residues in CSE abolished CSE nitrosylation or sulfhydration and prevented its binding to L\u2010homocysteine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      Sulfhydration or nitrosylation of CSE represents a yin\/yang regulation of catalysis or binding to L\u2010homocysteine. H\n                      <jats:sub>2<\/jats:sub>\n                      S donor treatment enhanced CSE sulfhydration, thus lowering serum L\u2010homocysteine, which contributed in part to the anti\u2010atherosclerosis effects in ApoE\u2010knockout mice with hyperhomocysteinemia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.14719","type":"journal-article","created":{"date-parts":[[2019,5,29]],"date-time":"2019-05-29T07:30:23Z","timestamp":1559115023000},"page":"3180-3192","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine \u03b3 lyase S\u2010sulfhydration in ApoE\u2010knockout atherosclerotic mice"],"prefix":"10.1111","volume":"176","author":[{"given":"Jinhui","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, MOE Key Lab of Cardiovascular Sciences, School of Basic Medical Science, State Key Laboratory of Natural and Biomimetic Drugs, the School of Pharmaceutical Sciences Peking University  Beijing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengjiao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Center for Noncoding RNA Medicine, MOE Key Lab of Cardiovascular Sciences, School of Basic Medical Science, State Key Laboratory of Natural and Biomimetic Drugs, the School of Pharmaceutical Sciences Peking University  Beijing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyue","family":"Li","sequence":"additional","affiliation":[{"name":"Hypertension Center, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease National Center for Cardiovascular Diseases  Beijing P.R. 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