title: Hydrogen sulfide upregulates KATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats.
abstract: The study was designed to investigate whether H2S could upregulate expression of KATP channels in vascular smooth muscle cells (VSMCs), and by this mechanism enhances vasorelaxation in spontaneously hypertensive rats (SHR). Blood pressure, vascular structure, and vasorelaxation were analyzed. Plasma H2S was detected using polarographic sensor. SUR2B and Kir6.1 expressions were detected in VSMCs of SHR and in A7r5 cells as well as primarily cultured ASMCs using real-time PCR, western blot, immunofluorescence, and confocal imaging. Nuclear translocation of forkhead transcription factors FOXO1 and FOXO3a in ASMCs was detected using laser confocal microscopy, and their binding activity with SUR2B and Kir6.1 promoters was examined by chromatin immunoprecipitation. SHR developed hypertension at 18 weeks. They showed downregulated vascular SUR2B and Kir6.1 expressions in association with a decreased plasma H2S level. H2S donor, however, could upregulate vascular SUR2B and Kir6.1 expressions, causing a left shift of the vasorelaxation curve to pinacidil and lowered tail artery pressure in the SHR. Also, H2S antagonized endothelin-1 (ET-1)-inhibited KATP expression in A7r5 cells and cultured ASMCs. Mechanistically, H2S inhibited ET-1-stimulated p-FOXO1 and p-FOXO3a expressions (inactivated forms), but increased their nuclear translocation and the ET-1-inhibited binding of FOXO1 and FOXO3a with Kir6.1 and SUR2B promoters in ASMCs. Hence, H2S promotes vasorelaxation of SHR, at least in part, through upregulating the expression of KATP subunits by inhibiting phosphorylation of FOXO1 and FOXO3a, and stimulating FOXO1 and FOXO3a nuclear translocation and their binding activity with SUR2B and Kir6.1 promoters.
  
  
  CONCLUSIONS
  H2S increased vascular SUR2B and Kir6.1 expression of SHR, promoting vasorelaxation. H2S antagonized ET-1-inhibited KATP expression in A7r5 cells and cultured ASMCs. H2S inhibited ET-1-induced FOXO1 and FOXO3a phosphorylation in ASMCs. H2S promoted FOXO1 and FOXO3a nuclear translocation and binding with target gene promoters.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Xi-An Men Street No. 1, West District, Beijing, 100034, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Huang
authors.forename: Rongyuan
authors.initials: R
authors.lastname: Zhang
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zong
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Shasha
authors.initials: S
authors.lastname: Feng
authors.forename: Angie Dong
authors.initials: AD
authors.lastname: Liu
authors.forename: Lukas
authors.initials: L
authors.lastname: Holmberg
authors.forename: Die
authors.initials: D
authors.lastname: Liu
authors.forename: Chaoshu
authors.initials: C
authors.lastname: Tang
authors.forename: Junbao
authors.initials: J
authors.lastname: Du
authors.forename: Hongfang
authors.initials: H
authors.lastname: Jin
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D064426:Gasotransmitters / Q000097:blood / Q000627:therapeutic use*; D006862:Hydrogen Sulfide / Q000097:blood / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054086:KATP Channels / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D064233:Sulfonylurea Receptors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects; D000071161:Forkhead Box Protein O1
chemical_list: D019332:Endothelin-1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D064426:Gasotransmitters; D006862:Hydrogen Sulfide; D054086:KATP Channels; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D064233:Sulfonylurea Receptors; C577512:Abcc9 protein, rat; C499515:FOXO3 protein, rat; C092520:uK-ATP-1 potassium channel; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1