ORIGINAL ARTICLE Hydrogen sulfide upregulates K ATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats Yan Sun & Yaqian Huang & Rongyuan Zhang & Qinghua Chen & Jie Chen & Yanfang Zong & Jia Liu & Shasha Feng & Angie Dong Liu & Lukas Holmberg & Die Liu & Chaoshu Tang & Junbao Du & Hongfang Jin Received: 2 February 2014 /Revised: 26 October 2014 /Accepted: 3 November 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract The study was designed to investigate whether H 2 S could upregulate expression of K ATP 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 H 2 S was detected using polarographic sen- sor. 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, immunofluores- cence, 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 devel- oped hypertension at 18 weeks. They showed downregulated vascular SUR2B and Kir6.1 expressions in association with a decreased plasma H 2 S level. H 2 S donor, however, could up- regulate 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, H 2 S antagonized endothelin-1 (ET-1)-inhibited K ATP expression in A7r5 cells and cultured ASMCs. Mechanistically, H 2 S 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, H 2 S promotes vasore- laxation of SHR, at least in part, through upregulating the expression of K ATP 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. Key messages & H 2 S increased vascular SUR2B and Kir6.1 expression of SHR, promoting vasorelaxation. & H 2 S antagonized ET-1-inhibited K ATP expression in A7r5 cells and cultured ASMCs. & H 2 S inhibited ET-1-induced FOXO1 and FOXO3a phos- phorylation in ASMCs. & H 2 S promoted FOXO1 and FOXO3a nuclear transloca- tion and binding with target gene promoters. Keywords Hydrogensulfide . Vasorelaxation . ATP-sensitive potassium channels . Smooth muscle cell . Hypertension Yan Sun, Yaqian Huang, and Rongyuan Zhang contributed equally to this work Electronic supplementary material The online version of this article (doi:10.1007/s00109-014-1227-1) contains supplementary material, which is available to authorized users. Y. Sun : Y. Huang : R. Zhang : Q. Chen : Y. Zong : J. Liu : S. Feng : D. Liu : J. Du : H. Jin (*) Department of Pediatrics, Peking University First Hospital, Xi-An Men Street No. 1, West District, Beijing 100034, China e-mail: jinhongfang51@126.com J. Chen Department of Pediatrics, Provincial School of Clinical Medicine, Fujian Medical University, Fuzhou, China A. D. Liu : L. Holmberg Department of Medical and Health Sciences, Linköping University, Linköping, Sweden C. Tang Institute of Cardiovascular Diseases, Peking University First Hospital, Beijing, China C. Tang : J. Du Key Laboratory of Molecular Cardiology, Ministry of Education, Beijing, China J Mol Med DOI 10.1007/s00109-014-1227-1