Regulation of vascular smooth muscle cell differentiation by fatty acid composition

• Project/Area Number: 16H05294
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Gunma University
• Principal Investigator: Kurabayashi Masahiko 群馬大学, 大学院医学系研究科, 教授 (00215047)
• Co-Investigator(Kenkyū-buntansha): 磯 達也 群馬大学, 大学院医学系研究科, 研究員 (10400756)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
• Keywords: 動脈硬化 / 血管平滑筋 / エネルギー代謝 / 脂肪酸 / 血管平滑筋細胞 / 形質変換 / 転写因子 / 糖尿病 / KLF4 / AMPK

Outline of Final Research Achievements

We investigated the role of elongation of long-chain fatty acid (LCFA) member 6 (Elovl6), a rate-limiting enzyme catalyzing the elongation of saturated and monounsaturated LCFA, in the regulation of phenotypic switching of VSMC.We demonstrate for the first time that dysregulation of Elovl6-driven LCFA 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 post-angioplasty restenosis.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、血管平滑筋細胞に留まらず、さまざまな細胞における脂肪酸代謝の変化が細胞の増殖や分化調節にどのような役割を持つかに関しての研究と繋がり、再生医学やがん細胞の生物学にも波及しうる成果を提供しうると考えている。

Research Products

• [Journal Article] Exercise endurance capacity ismarkedly reduced due to impaired energy homeostasis during prolonged fasting inFABP4/5 deficient mice. (2019)
  • Author(s): Iso T, Haruyama H, Sunaga H, Matsui M, Matsui H, Tanaka R, Umbarawan Y, Syamsunarno MRAA, Yokoyama T, Kurabayashi M.
  • Journal Title: BMC Physiol. Volume: 19(1) Issue: 1 Pages: 1-10
  • DOI: 10.1186/s12899-019-0038-6
  • Peer Reviewed / Open Access
• [Journal Article] Circulating FABP4 is eliminated by the kidney via glomerular filtration followed by megalin-mediated reabsorption (2018)
  • Author(s): Shrestha S, Sunaga H, Hanaoka H, Yamaguchi A, Kuwahara S, Umbarawan Y, Nakajima K, Machida T, Murakami M, Saito A, Tsushima Y, Kurabayashi M, Iso T
  • Journal Title: Sci Rep Volume: 8(1) Issue: 1 Pages: 16451-16451
  • DOI: 10.1038/s41598-018-34902-w
  • Peer Reviewed / Open Access
• [Journal Article] CD36 is indispensable for nutrient homeostasis and endurance exercise capacity during prolonged fasting (2018)
  • Author(s): Iso T, Haruyama H, Sunaga H, Matsui H, Matsui M, Tanaka R, Umbarawan Y, Syamsunarno MRAA, Putri M, Yamaguchi A, Hanaoka H, Negishi K, Yokoyama T, Kurabayashi M
  • Journal Title: Physiol Rep Volume: 6(19) Issue: 19 Pages: e13884-e13884
  • DOI: 10.14814/phy2.13884
  • Peer Reviewed / Open Access
• [Journal Article] Myocardial fatty acid uptake through CD36 is indispensable for sufficient bioenergetic metabolism to prevent progression of pressure overload-induced heart failure (2018)
  • Author(s): Umbarawan Y, Syamsunarno MRAA, Koitabashi N, Obinata H, Yamaguchi A, Hanaoka H, Hishiki T, Hayakawa N, Sano M, Sunaga H, Matsui H, Tsushima Y, Suematsu M, Kurabayashi M, Iso T
  • Journal Title: Sci Rep Volume: 8(1) Issue: 1 Pages: 12035-12035
  • DOI: 10.1038/s41598-018-30616-1
  • Peer Reviewed / Open Access
• [Journal Article] Glucose is preferentially utilized for biomass synthesis in pressure-overloaded hearts: Evidence from fatty acid binding protein-4 and -5 knockout mice. (2018)
  • Author(s): Umbarawan Y, Syamsunarno MRAA, Koitabashi N, Yamaguchi A, Hanaoka H, Hishiki T, Nagahata-Naito Y, Obinata H, Sano M, Sunaga H, Matsui H, Tsushima Y, Suematsu M, Kurabayashi M, Iso T
  • Journal Title: Cardiovasc Res. Volume: - Issue: 8 Pages: 1132-1144
  • DOI: 10.1093/cvr/cvy063
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Robust suppression of cardiac energy catabolism with marked accumulation of energy substrates during lipopolysaccharide-induced cardiac dysfunction in mice. (2017)
  • Author(s): Umbarawan Y, Syamsunarno MR, Obinata H, Yamaguchi A, Sunaga H, Matsui H, Hishiki T, Matsuura T, Koitabashi N, Obokata M, Hanaoka H, Haque A, Kunimoto F, Tsushima Y, Suematsu M, Kurabayashi M, Iso T
  • Journal Title: Metabolism, clinical and experimental. Volume: - Pages: 47-57
  • DOI: 10.1016/j.metabol.2017.09.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells. (2016)
  • Author(s): Nakahara T, Kawai-Kowase K, Matsui H, Sunaga H, Utsugi T, Iso T, Arai M, Tomono S, Kurabayashi M.
  • Journal Title: Atherosclerosis Volume: 253 Pages: 102-110
  • Acknowledgement Compliant
• [Journal Article] 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/Krupple-Like Factor 4 (AMPK/KLF4) Signaling. (2016)
  • Author(s): Sunaga H, Matsui H, Anjo S, Syamsunarno MR, Koitabashi N, Iso T, Matsuzaka T, Shimano H, Yokoyama T, Kurabayashi M
  • Journal Title: J Am Heart Assoc. Volume: 5 Issue: 12
  • DOI: 10.1161/jaha.116.004014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Circlating Ketone Body as a Novel biomarker for Worse Clinical Outcomes in Hemodialysis Patient (2018)
  • Author(s): 須永浩章、小保方 優、根岸一明、小川哲也、磯 達也、小板橋紀通、倉林正彦
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Glucose is Preferably Utilized for Biomass Synthesis Rather than ATP Production in Pressure-overloaded CD36 Deficient Heart (2018)
  • Author(s): Yogi Umbarawan,Mas Rizky AA Syamsunarno,Koitabashi N,Kurabayashi M,Iso T.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Identificaion and Molecular Mechanisms of Fibroblast Growth Factor 21 as a Novel Biomarker for Metabolic Stress in Acute Myocardial Infarction. (2018)
  • Author(s): Koitabashi N,Sunaga H,Matsui H,Iso T,Kurabayashi M
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Elevation of Serum Fibroblast Growth Factor 21 in Patients With Acute Myocardial Infarction:A Potential Role of Ampk Activation Following Sympathetic Overdrive (2018)
  • Author(s): Sunaga H.,Koitabashi N.,Matsui H.,Iso T.,Yokoyama T.,Kurabayashi M.
  • Organizer: American Heart Association Scientific Meeting
  • Int'l Joint Research
• [Presentation] Inhibition of Fatty Acid Synthase Suppresses Vascular Smooth Muscle Cell Proliferation and Neointimal Formation:Potential Therapeutic Target in Atehrosclerosis (2018)
  • Author(s): Matsui H,Sunaga H,Iso T,Yokoyama T,Kurabayashi M.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Identificaion and Molecular Mechanisms of Fibroblast Growth Factor 21 as a Novel Biomarker for Metabolic Stress in Acute Myocardial Infarction (2018)
  • Author(s): Koitabashi N,Sunaga H,Matsui H,Iso T,Kurabayashi M
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] A shift of energy substrate shift from fatty acids to glucose exacerbates cardiac dysfunction during pressure overload: A lesson learned from fatty acid binding protein-4 and -5 knockout mice (2017)
  • Author(s): Yogi Umbarawan
  • Organizer: 日本循環器学会
  • Place of Presentation: 金沢市
  • Year and Date: 2017-03-17