title: Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4.
abstract: Fatty acid-binding protein (FABP) 4 is an adipocytokine mainly expressed in adipocyte and macrophage. Blood FABP4 is related not only to metabolic disorders including insulin resistance and atherosclerosis but also increased blood pressure. We tested the hypothesis that FABP4 plays roles in pathogenesis of hypertension development including proliferation, migration, and inflammation of vascular smooth muscle cells (SMCs) as well as contractile reactivity. FABP4 alone had no influence on proliferation, migration, and inflammation of rat mesenteric arterial SMCs, while it significantly enhanced smooth muscle contraction and increases of systolic blood pressure (SBP) induced by noradrenaline (NA). BMS-309403, an FABP4 inhibitor, significantly inhibited platelet-derived growth factor-BB-induced DNA synthesis and migration via preventing p38 and HSP27 activation. Further, BMS-309403 significantly inhibited tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 as well as monocyte adhesion via preventing NF-κB activation. Interestingly, SMCs do not express FABP4. Long-term treatment of spontaneously hypertensive rats (SHR) with BMS-309403 significantly inhibited impaired relaxation in isolated mesenteric arteries and left ventricular hypertrophy, while it had no influence on SBP. We for the first time showed that FABP4 acutely enhances NA-induced increases of SBP possibly through the enhancement of peripheral arterial contractility. BMS-309403 prevents proliferation, migration, and inflammatory responses of SMCs, although exogenous application of FABP4 has no influence on the cellular responses. Furthermore, we demonstrated that long-term treatment with BMS-309403 partially improves the pathological conditions of SHR. These results indicate that BMS-309403 would be useful for developing a new pharmacotherapeutic agent against obesity-associated hypertension and complications.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Okamura
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Otani
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekiguchi
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kogane
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kakuda
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Yuzaburo
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan. yamawaki@vmas.kitasato-u.ac.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors*; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D001713:Biphenyl Compounds; C524662:FABP4 protein, rat; D050556:Fatty Acid-Binding Proteins; D016328:NF-kappa B; D020011:Protective Agents; D011720:Pyrazoles
keywords: Adipocytokine; Contractility; Hypertension; Inflammation; Migration; Proliferation; Vascular smooth muscle