title: Sirtuin-6 inhibits cardiac fibroblasts differentiation into myofibroblasts via inactivation of nuclear factor κB signaling.
abstract: Differentiation of cardiac fibroblasts (CFs) into myofibroblasts represents a key event in cardiac fibrosis that contributes to pathologic cardiac remodeling. However, regulation of this phenotypic transformation remains elusive. Here, we show that sirtuin-6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent histone deacetylase, plays a role in the regulation of myofibroblast differentiation. SIRT6 expression was upregulated under pathologic conditions in angiotensin II (Ang II)-stimulated CFs and in myocardium of rat subjected to abdominal aortic constriction surgery. SIRT6 depletion by RNA interference (small interfering RNA [siRNA]) in CFs resulted in increased cell proliferation and extracellular matrix deposition. Further examination of SIRT6-depleted CFs demonstrated significantly higher expression of α-smooth muscle actin (α-SMA), the classical marker of myofibroblast differentiation, and increased formation of focal adhesions. Notably, SIRT6 depletion further exacerbated Ang II-induced myofibroblast differentiation. Overexpression of SIRT6 restored α-SMA expression in SIRT6-depleted or Ang II-treated CFs. Moreover, SIRT6 depletion induced the DNA binding activity and transcriptional activity of nuclear factor κB (NF-κB). Importantly, using an NF-κB p65 siRNA or pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB activity, reversed the expression of phenotypic markers of myofibroblasts. Our findings unravel a novel role of SIRT6 as a key modulator in the phenotypic conversion of CFs to myofibroblasts.
authors.affiliation: School of Nursing, Guangdong Pharmaceutical University, Guangzhou, China; Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Kunming
authors.initials: K
authors.lastname: Tian
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.affiliation: School of Nursing, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Tianhui
authors.initials: T
authors.lastname: You
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. Electronic address: liupq@mail.sysu.edu.cn.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D037761:Sirtuins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D000804:Angiotensin II; D037761:Sirtuins; C560607:sirtuin 6, rat