Open AccessElongation 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 / KLF 4) Signaling
Author(s) -
Sunaga Hiroaki,
Matsui Hiroki,
Anjo Saki,
Syamsunarno Mas Risky A. A.,
Koitabashi Norimichi,
Iso Tatsuya,
Matsuzaka Takashi,
Shimano Hitoshi,
Yokoyama Tomoyuki,
Kurabayashi Masahiko
Publication year - 2016
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.116.004014
Subject(s) - ampk , gene knockdown , vascular smooth muscle , microbiology and biotechnology , amp activated protein kinase , fatty acid , protein kinase a , downregulation and upregulation , pi3k/akt/mtor pathway , biology , signal transduction , kinase , endocrinology , biochemistry , apoptosis , smooth muscle , gene
Background 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 ( VSMC s). 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 . Methods and Results Neointima formation following wire injury was markedly inhibited in Elovl6‐null (Elovl6 −/− ) mice, and cultured VSMC s with si RNA ‐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 ( KLF 4) expression in VSMC , and KLF 4 knockdown significantly attenuated AMPK ‐induced phenotypic switching of VSMC , indicating that KLF 4 is a bona fide target of AMPK . Conclusions 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 / KLF 4 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.