title: The vasodilatory effect of sulfur dioxide via SGC/cGMP/PKG pathway in association with sulfhydryl-dependent dimerization.
abstract: The present study was designed to explore the role of soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/PKG pathway in sulfur dioxide (SO2)-induced vasodilation. We showed that SO2 induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted rat aortic rings in association with an increase in cGMP concentration, whereas l-aspartic acid β-hydroxamate (HDX), an inhibitor of SO2 synthase, contracted rings in a dose-dependent manner. Pretreatment of aortic rings with the sGC inhibitor ODQ (30 μM) attenuated the vasodilatory effects of SO2, suggesting the involvement of cGMP pathway in SO2-induced vasodilation. Mechanistically, SO2 upregulated the protein levels of sGC and PKG dimers, while HDX inhibited it, indicating SO2 could promote cGMP synthesis through sGC activation. Furthermore, the dimerization of sGC and PKG and vasodilation induced by SO2 in precontracted rings were significantly prevented by thiol reductants dithiothreitol (DTT). In addition, SO2 reduced the activity of phosphodiesterase type 5 (PDE5), a cGMP-specific hydrolytic enzyme, implying that SO2 elevated cGMP concentration by inhibiting its hydrolysis. Hence, SO2 exerted its vasodilatory effects at least partly by promoting disulfide-dependent dimerization of sGC and PKG, resulting in an activated sGC/cGMP/PKG pathway in blood vessels. These findings revealed a new mode of action and mechanisms by which SO2 regulated the vascular tone.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden;
authors.forename: Angie Dong
authors.initials: AD
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Qingyou
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, People's Republic of China;
authors.forename: Bin
authors.initials: B
authors.lastname: Geng
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Centre, Beijing, People's Republic of China;
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, Beijing Shijitan Hospital, Beijing, People's Republic of China; and.
authors.forename: Shuxu
authors.initials: S
authors.lastname: Du
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China;
authors.forename: Pan
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Key Laboratory of Cardiovascular Sciences, Ministry of Education, Beijing, People's Republic of China.
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China; Key Laboratory of Cardiovascular Sciences, Ministry of Education, Beijing, People's Republic of China.
authors.forename: Junbao
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing, People's Republic of China; jinhongfang51@126.com.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Jin
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D008297:Male; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013458:Sulfur Dioxide / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D013438:Sulfhydryl Compounds; D014665:Vasodilator Agents; D013458:Sulfur Dioxide; D017869:Cyclic GMP-Dependent Protein Kinases; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: PKG; SGC; cGMP; dimer; sulfur dioxide; vasodilation