title: Short-term treatment with a 2-carba analog of cyclic phosphatidic acid induces lowering of plasma cholesterol levels in ApoE-deficient mice.
abstract: Plasma cholesterol levels are associated with an increased risk of developing atherosclerosis. An elevated low-density lipoprotein cholesterol (LDL-C) level is a hallmark of hypercholesterolemia in metabolic syndrome. Our previous study suggested that when acetylated LDL (AC-LDL) was co-applied with a PPARγ agonist, rosiglitazone (ROSI), many oil red O-positive macrophages could be observed. However, addition of cyclic phosphatidic acid (cPA) to ROSI-stimulated macrophages completely abolished oil red O-stained cells, indicating that cPA inhibits PPARγ-regulated AC-LDL uptake. This study aimed to determine whether metabolically stabilized cPA, in the form of a carba-derivative of cPA (2ccPA), could reduce plasma cholesterol levels and affect the expression of genes related to atherosclerosis in apolipoprotein E-knockout (apoE(-/-)) mice. 2ccPA reduced LDL-C levels in these mice (n = 3) from 460 to 330 mg/ml, from 420 to 350 mg/ml, and 420 to 281 mg/ml under a western-type diet. 2ccPA also reduced expression of lipid metabolism-related genes, cytokines, and chemokines in ApoE-deficient mice on a high-fat diet. Taken together, these results suggest that 2ccPA governs anti-atherogenic activities in the carotid arteries of apoE-deficient mice.
authors.affiliation: Department of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. Electronic address: ttamotsu@nagasaki-u.ac.jp.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Tsukahara
authors.affiliation: Institute for Biomedical Sciences, Shinshu University Interdisciplinary Cluster for Cutting Edge Research, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Haniu
authors.affiliation: Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Ina-machi, Saitama 362-0806, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Endowed Research Division of Human Welfare Sciences, Ochanomizu University, 2-1-1, Ohtsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Murakmi-Murofushi
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics; D002339:Carotid Arteries / Q000473:pathology; D008078:Cholesterol, LDL / Q000097:blood*; D004195:Disease Models, Animal; D018450:Disease Progression; D007249:Inflammation; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D010712:Phosphatidic Acids / Q000008:administration & dosage* / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000819:agonists; D014280:Triglycerides / Q000378:metabolism
chemical_list: C000610718:1-oleoyl-2-carba cyclic phosphatidic acid; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D047495:PPAR gamma; D010712:Phosphatidic Acids; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone
keywords: Atherosclerosis; Cholesterol; Cyclic phosphatidic acid; High-density lipoprotein cholesterol (HDL-C); Low-density lipoprotein cholesterol (LDL-C)