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
BackgroundFatty 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...
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| Format: | Article |
| Language: | English |
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Wiley
2016-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.004014 |
| _version_ | 1818315239937015808 |
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| author | Hiroaki Sunaga Hiroki Matsui Saki Anjo Mas Risky A. A. Syamsunarno Norimichi Koitabashi Tatsuya Iso Takashi Matsuzaka Hitoshi Shimano Tomoyuki Yokoyama Masahiko Kurabayashi |
| author_facet | Hiroaki Sunaga Hiroki Matsui Saki Anjo Mas Risky A. A. Syamsunarno Norimichi Koitabashi Tatsuya Iso Takashi Matsuzaka Hitoshi Shimano Tomoyuki Yokoyama Masahiko Kurabayashi |
| author_sort | Hiroaki Sunaga |
| collection | DOAJ |
| description | BackgroundFatty 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. Methods and ResultsNeointima 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. ConclusionsWe 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. |
| first_indexed | 2024-12-13T09:02:23Z |
| format | Article |
| id | doaj.art-ded9bf33d50c4ba6b3f572861e2ab05b |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T09:02:23Z |
| publishDate | 2016-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-ded9bf33d50c4ba6b3f572861e2ab05b2022-12-21T23:53:09ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-12-0151210.1161/JAHA.116.004014Elongation 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) SignalingHiroaki Sunaga0Hiroki Matsui1Saki Anjo2Mas Risky A. A. Syamsunarno3Norimichi Koitabashi4Tatsuya Iso5Takashi Matsuzaka6Hitoshi Shimano7Tomoyuki Yokoyama8Masahiko Kurabayashi9Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, JapanDepartment of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, JapanDepartment of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, JapanDepartment of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, JapanDepartment of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, JapanDepartment of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, JapanDepartment of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, JapanDepartment of Medicine and Biological Sciences, Gunma University Graduate School of Medicine, Maebashi, JapanBackgroundFatty 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. Methods and ResultsNeointima 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. ConclusionsWe 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.https://www.ahajournals.org/doi/10.1161/JAHA.116.004014Elovl6fatty acidneointimal hyperplasiaproliferationsmooth muscle cell |
| spellingShingle | Hiroaki Sunaga Hiroki Matsui Saki Anjo Mas Risky A. A. Syamsunarno Norimichi Koitabashi Tatsuya Iso Takashi Matsuzaka Hitoshi Shimano Tomoyuki Yokoyama Masahiko Kurabayashi 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 Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease Elovl6 fatty acid neointimal hyperplasia proliferation smooth muscle cell |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 kruppel like factor 4 ampk klf4 signaling |
| topic | Elovl6 fatty acid neointimal hyperplasia proliferation smooth muscle cell |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.004014 |
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