title: Elongation of Long-Chain Fatty Acid Family Member 6 (Elovl6)-Driven Fatty Acid Metabolism Regulates Vascular Smooth Muscle Cell Phenotype Through AMP-Activated Protein Kinase/Krüppel-Like Factor 4 (AMPK/KLF4) Signaling.
abstract: Fatty acids constitute the critical components of cell structure and function, and dysregulation of fatty acid composition may exert diverging vascular effects including proliferation, migration, and differentiation of vascular smooth muscle cells (VSMCs). However, direct evidence for this hypothesis has been lacking. We investigated the role of elongation of long-chain fatty acid member 6 (Elovl6), a rate-limiting enzyme catalyzing the elongation of saturated and monounsaturated long-chain fatty acid, in the regulation of phenotypic switching of VSMC.
  
  
  
  Neointima formation following wire injury was markedly inhibited in Elovl6-null (Elovl6-/-) mice, and cultured VSMCs with siRNA-mediated knockdown of Elovl6 was barely responsive to PDGF-BB. Elovl6 inhibition induced cell cycle suppressors p53 and p21 and reduced the mammalian targets of rapamycin (mTOR) phosphorylation and VSMC marker expression. These changes are ascribed to increased palmitate levels and reduced oleate levels, changes that lead to reactive oxygen species (ROS) production and resulting AMP-activated protein kinase (AMPK) activation. Notably, Elovl6 inhibition robustly induced the pluripotency gene Krüppel-like factor 4 (KLF4) expression in VSMC, and KLF4 knockdown significantly attenuated AMPK-induced phenotypic switching of VSMC, indicating that KLF4 is a bona fide target of AMPK.
  
  
  
  We demonstrate for the first time that dysregulation of Elovl6-driven long-chain fatty acid metabolism induces phenotypic switching of VSMC via ROS production and AMPK/KLF4 signaling that leads to growth arrest and downregulation of VSMC marker expression. The modulation of Elovl6-mediated cellular processes may provide an intriguing approach for tackling atherosclerosis and postangioplasty restenosis.
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan.|Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sunaga
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Anjo
authors.affiliation: Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan.|Department of Biochemistry, Faculty of Medicine Universitas Padjadjaran, Jatinangor, Indonesia.
authors.forename: Mas Risky A A
authors.initials: MR
authors.lastname: Syamsunarno
authors.affiliation: Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.affiliation: Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Iso
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.|Graduate School of Comprehensive Human Sciences International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Japan tyokoyama@gunma-u.ac.jp mkuraba@gunma-u.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Department of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, Japan tyokoyama@gunma-u.ac.jp mkuraba@gunma-u.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; D005227:Fatty Acids; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012313:RNA; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D055372:AMP-Activated Protein Kinases
keywords: Elovl6; fatty acid; neointimal hyperplasia; proliferation; smooth muscle cell