title: Statins upregulate cystathionine γ-lyase transcription and H2S generation via activating Akt signaling in macrophage.
abstract: Hydrogen sulfide (H2S), the third gaseous transmitter, is implicated in various pathophysiologic processes. In the cardiovascular system, H2S exerts effects of cardioprotection, vascular tone regulation, and atherogenesis inhibition. Recent studies demonstrated that atorvastatin, the inhibitor of 3-hydroxyl-3-methyl coenzyme A reductase, affected H2S formation in kidney and other organs. However, the underlying mechanisms are not fully understood. In this study, we examined the effects of three different statins (fluvastatin, atorvastatin and pravastatin) on H2S formation in raw264.7 macrophages. There was a remarkable rise in H2S level in fluvastatin- and atorvastatin-stimulated macrophages, while pravastatin failed to show any significant effect on it. Moreover, fluvastatin and atorvastatin enhanced the mRNA and protein expression of cystathionine γ-lyase (CSE) in dose- and time-dependent manners. Fluvastatin also markedly enhanced the CSE activity. However, fluvastatin did not alter the mRNA or protein expression of another H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase. Blockade of CSE with its inhibitor dl-propargylglycine (PAG) or siRNA markedly reduced the H2S level in fluvastatin-stimulated macrophages. In addition, fluvastatin elevated Akt phosphorylation, which occurred as early as 15 min after treatment, peaked at 1h, and lasted at least 3h. Both PI3K inhibitor LY294002 (10 μM) and Akt inhibitor perifosine (10μM) were able to reverse the increases of CSE mRNA and H2S production in fluvastatin-stimulated macrophages. Last, we showed that fluvastatin reduced the mRNA levels of pro-inflammatory molecules such as IL-1β and MCP-1 in LPS-treated macrophages, which were completely reversed by CSE inhibitor PAG. Taken together, the findings demonstrate that statins may up-regulate CSE expression/activity and subsequently elevate H2S generation by activating Akt signaling pathway and also imply that CSE-H2S pathway plays a critical role in the anti-inflammation elicited by statins.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China; Department of Neurology, The Affiliated Wujiang Hospital of Nantong University, Suzhou 215200, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Hua-Ping
authors.initials: HP
authors.lastname: Du
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: You
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Cao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: liucf@suda.edu.cn.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China; Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China. Electronic address: hulifang@suda.edu.cn.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Hu
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D002460:Cell Line; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D017035:Pravastatin / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011758:Pyrroles; D012333:RNA, Messenger; D000077340:Fluvastatin; D000069059:Atorvastatin; D051057:Proto-Oncogene Proteins c-akt; D003542:Cystathionine gamma-Lyase; D017035:Pravastatin; D006862:Hydrogen Sulfide
keywords: 3-Mercaptopyruvate sulfurtransferase; Akt; Cystathionine γ-lyase; Hydrogen sulfide; Macrophage; Statins