title: Free Fatty Acids Induce Autophagy and LOX-1 Upregulation in Cultured Aortic Vascular Smooth Muscle Cells.
abstract: Elevation of free fatty acids (FFAs) is known to affect microvascular function and contribute to obesity-associated insulin resistance, hypertension, and microangiopathy. Proliferative and synthetic vascular smooth muscle cells (VSMCs) increase intimal thickness and destabilize atheromatous plaques. This study aimed to investigate whether saturated palmitic acid (PA) and monounsaturated oleic acid (OA) modulate autophagy activity, cell proliferation, and vascular tissue remodeling in an aortic VSMC cell line. Exposure to PA and OA suppressed growth of VSMCs without apoptotic induction, but enhanced autophagy flux with elevation of Beclin-1, Atg5, and LC3I/II. Cotreatment with autophagy inhibitors potentiated the FFA-suppressed VSMC growth and showed differential actions of PA and OA in autophagy flux retardation. Both FFAs upregulated lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) but only OA increased LDL uptake by VSMCs. Mechanistically, FFAs induced hyperphosphorylation of Akt, ERK1/2, JNK1/2, and p38 MAPK. All pathways, except OA-activated PI3K/Akt cascade, were involved in the LOX-1 upregulation, whereas blockade of PI3K/Akt and MEK/ERK cascades ameliorated the FFA-induced growth suppression on VSMCs. Moreover, both FFAs exhibited tissue remodeling effect through increasing MMP-2 and MMP-9 expression and their gelatinolytic activities, whereas high-dose OA significantly suppressed collagen type I expression. Conversely, siRNA-mediated LOX-1 knockdown significantly attenuated the OA-induced tissue remodeling effects in VSMCs. In conclusion, OA and PA enhance autophagy flux, suppress aortic VSMC proliferation, and exhibit vascular remodeling effect, thereby leading to the loss of VSMCs and interstitial ECM in vascular walls and eventually the instability of atheromatous plaques. J. Cell. Biochem. 118: 1249-1261, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Cheng-I
authors.initials: CI
authors.lastname: Cheng
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yueh-Hong
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Po-Han
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, Taiwan.
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chou
authors.affiliation: Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
mesh_terms: D000818:Animals; D001011:Aorta; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005227:Fatty Acids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D051381:Rats; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D005227:Fatty Acids; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E; D019301:Oleic Acid; D019308:Palmitic Acid
keywords: AUTOPHAGY; LECTIN-LIKE OXIDIZED LDL RECEPTOR; OLEIC ACID; PALMITIC ACID; SIGNAL TRANSDUCTION; VASCULAR REMODELING