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Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4

  • Signaling and cell physiology
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

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.

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Acknowledgements

This study was supported by Grants for Scientific Research from Japan Society for the Promotion of Science and School of Veterinary Medicine, The Kitasato University.

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Authors and Affiliations

  1. Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan

    Yuta Okamura, Kosuke Otani, Akihiro Sekiguchi, Taisuke Kogane, Chiharu Kakuda, Yuzaburo Sakamoto, Tomoko Kodama, Muneyoshi Okada & Hideyuki Yamawaki

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  1. Yuta Okamura
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  2. Kosuke Otani
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  3. Akihiro Sekiguchi
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Correspondence to Hideyuki Yamawaki.

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Yuta Okamura and Kosuke Otani are co-first authors.

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Okamura, Y., Otani, K., Sekiguchi, A. et al. Vasculo-protective effect of BMS-309403 is independent of its specific inhibition of fatty acid-binding protein 4. Pflugers Arch - Eur J Physiol 469, 1177–1188 (2017). https://doi.org/10.1007/s00424-017-1976-0

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