title: Hydrogen Sulfide Regulates Krüppel-Like Factor 5 Transcription Activity via Specificity Protein 1 S-Sulfhydration at Cys664 to Prevent Myocardial Hypertrophy.
abstract: Hydrogen sulfide (H2S) is a gasotransmitter that regulates multiple cardiovascular functions. Krüppel-like factor 5 (KLF5) exerts diverse functions in the cardiovascular system. Whether and how H2S regulates KLF5 in myocardial hypertrophy is unknown.
  
  
  
  In our study, hypertrophic myocardial samples in the clinic were collected and underwent histological and molecular biological analysis. Spontaneously hypertensive rats and neonatal rat cardiomyocytes were studied for functional and signaling responses to GYY4137, an H2S-releasing compound. Expression of cystathionine γ-lyase, a principal enzyme for H2S generation in heart, decreased in human hypertrophic myocardium, whereas KLF5 expression increased. After GYY4137 administration for 4 weeks, myocardial hypertrophy was inhibited in spontaneously hypertensive rats, as demonstrated by improvement in cardiac structural parameters, heart mass, size of cardiac myocytes, and expression of atrial natriuretic peptide. H2S diminished expression of KLF5 in myocardium of spontaneously hypertensive rats and in hypertrophic cardiomyocytes. H2S also inhibits platelet-derived growth factor A promoter activity, decreased recruitment of KLF5 to the platelet-derived growth factor A promoter, and reduced atrial natriuretic peptide expression in angiotensin II-stimulated cardiomyocytes, and these effects are suppressed by KLF5 knockdown. KLF5 promoter activity and KLF5 expression was also reversed by H2S. H2S increased the S-sulfhydration on specificity protein 1 in cardiomyocytes. Moreover, H2S decreased KLF5 promoter activity; reduced KLF5 mRNA expression; attenuated specificity protein 1 binding activity with KLF5 promoter; and inhibited hypertrophy after specificity protein 1 mutated at Cys659, Cys689, and Cys692 but not Cys664 overexpression.
  
  
  
  These findings suggest that H2S regulates KLF5 transcription activity via specificity protein 1 S-sulfhydration at Cys664 to prevent myocardial hypertrophy.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Meng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China Department of Pathology, Jincheng People's Hospital, Jincheng, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xie
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA.
authors.forename: Chung-Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA.
authors.forename: Ming
authors.initials: M
authors.lastname: Xian
authors.affiliation: Faculty of Life Sciences, The University of Manchester, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cardiovascular Division, Department of Clinical Pharmacology, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Albert
authors.initials: A
authors.lastname: Ferro
authors.affiliation: Department of Biology, Laurentian University, Sudbury, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.affiliation: Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Third Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Centers for Metabolic Disease Research, Cardiovascular Research, and Thrombosis Research, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing, China yongji@njmu.edu.cn hanyi79@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China School of Pharmacy, Nanjing Medical University, Nanjing, China yongji@njmu.edu.cn hanyi79@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
mesh_terms: D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C529376:GYY 4137; C492214:KLF5 protein, human; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C075278:platelet-derived growth factor A; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: Krüppel‐like factor 5; S‐sulfhydration; atrial natriuretic peptide; hydrogen sulfide; myocardial hypertrophy; specificity protein 1