title: Newly developed PPAR-alpha agonist (R)-K-13675 inhibits the secretion of inflammatory markers without affecting cell proliferation or tube formation.
abstract: Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and has been implicated in inflammation. The vascular effects of activator for PPARs, particularly PPAR-alpha, on vascular cells remain to be fully elucidated. Therefore, we analyzed the hypothesis that newly developed (R)-K-13675 decreases the secretion of inflammatory markers without affecting cell proliferation or tube formation. Human coronary endothelial cells (HCECs) were maintained in different doses of (R)-K-13675 under serum starvation. After 20h, the levels of monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T expressed and secreted (RANTES), interleukin-6 (IL-6) and interferon-gamma (INF-gamma) secreted in the medium and nuclear factor kappa B (NFkappaB) in cell lysate were analyzed using enzyme-linked immunosorbent assays (ELISA). Upon treatment with (R)-K-13675 at 0, 10, 20, 50 and 100nM, with the inflammatory markers at 0nM as 100 (arbitrary units), MCP-1 levels were significantly suppressed (94+/-9, 88+/-2, 80+/-5 and 74+/-11, respectively). RANTES, IL-6 and INF-gamma levels were also significantly suppressed (RANTES: 92+/-2, 74+/-9, 64+/-7 and 60+/-2, respectively, IL-6: 97+/-2, 89+/-10, 82+/-1 and 66+/-7, respectively, INF-gamma: 98+/-7, 94+/-3, 76+/-8 and 64+/-8, respectively). NFkappaB levels were also decreased to 91+/-5, 90+/-5, 84+/-7 and 82+/-8, respectively. In addition, (R)-K-13675 did not affect HCEC proliferation or tube formation at up to 100nM. Thus, (R)-K-13675 was associated with the inhibition of inflammatory responses without affecting cell proliferation or angiogenesis, and subsequently may induce an anti-atherosclerotic effect.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kitajima
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Miura
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Mastuo
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism; D001583:Benzoxazoles / Q000494:pharmacology*; D001692:Biological Transport; D002087:Butyrates / Q000494:pharmacology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007797:Laminin / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists*; D011509:Proteoglycans / Q000737:chemistry
chemical_list: C540740:(R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid; D001583:Benzoxazoles; D002087:Butyrates; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D004338:Drug Combinations; D015850:Interleukin-6; D007797:Laminin; D016328:NF-kappa B; D047493:PPAR alpha; D011509:Proteoglycans; C059485:matrigel; D007371:Interferon-gamma; D003094:Collagen