title: Saturated fatty acid palmitate aggravates neointima formation by promoting smooth muscle phenotypic modulation.
abstract: OBJECTIVE
  Obesity is a major risk factor of atherosclerotic cardiovascular disease. Circulating free fatty acid levels are known to be elevated in obese individuals and, along with dietary saturated fatty acids, are known to associate with cardiovascular events. However, little is known about the molecular mechanisms by which free fatty acids are linked to cardiovascular disease.
  
  
  RESULTS
  We found that administration of palmitate, a major saturated free fatty acid, to mice markedly aggravated neointima formation induced by carotid artery ligation and that the neointima primarily consisted of phenotypically modulated smooth muscle cells (SMCs). In cultured SMCs, palmitate-induced phenotypic modulation was characterized by downregulation of SMC differentiation markers, such as SM α-actin and SM-myosin heavy chain, and upregulation of mediators involved in inflammation and remodeling of the vessel wall, such as platelet-derived growth factor B and matrix metalloproteinases. We also found that palmitate induced the expression of proinflammatory genes via a novel toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor-κB/NADPH oxidase 1/reactive oxygen species signaling pathway: nuclear factor-κB was activated by palmitate via toll-like receptor 4 and its adapter, MyD88, and once active, it transactivated Nox1, encoding NADPH oxidase 1, a major reactive oxygen species generator in SMCs. Pharmacological inhibition and small interfering RNA-mediated knockdown of the components of this signaling pathway mitigated the palmitate-induced upregulation of proinflammatory genes. More importantly, Myd88 knockout mice were resistant to palmitate-induced exacerbation of neointima formation.
  
  
  CONCLUSIONS
  Palmitate seems to promote neointima formation by inducing inflammatory phenotypes in SMCs.
authors: From the Department of Cardiovascular Medicine (H.S., K.E., K.F., S.M., M.S., I.K., I.M.), Translational Systems Biology and Medicine Initiative (K.F.), Graduate School of Medicine, and Graduate School of Pharmaceutical Sciences (N.K., H.A.), The University of Tokyo, Tokyo, Japan; Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan (Y.O.-T.); and Jichi Medical University, Tochigi, Japan (R.N.).
authors: Hua
authors: H
authors: Shen
authors: Kosei
authors: K
authors: Eguchi
authors: Nozomu
authors: N
authors: Kono
authors: Katsuhito
authors: K
authors: Fujiu
authors: Sahohime
authors: S
authors: Matsumoto
authors: Munehiko
authors: M
authors: Shibata
authors: Yumiko
authors: Y
authors: Oishi-Tanaka
authors: Issei
authors: I
authors: Komuro
authors: Hiroyuki
authors: H
authors: Arai
authors: Ryozo
authors: R
authors: Nagai
authors: Ichiro
authors: I
authors: Manabe
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D058426:Neointima / Q000139:chemically induced / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010168:Palmitates / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D005227:Fatty Acids; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010168:Palmitates; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse
keywords: fatty acid; inflammation; lipotoxicity; phenotypic modulation; reactive oxygen species; smooth muscle; toll-like receptor