Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada, Aomori, 034-8628, Japan.
Pflugers Arch. 2017 Sep;469(9):1177-1188. doi: 10.1007/s00424-017-1976-0. Epub 2017 Apr 13.
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.
脂肪酸结合蛋白（FABP）4 是一种主要在脂肪细胞和巨噬细胞中表达的脂肪细胞因子。血液 FABP4 不仅与代谢紊乱有关，包括胰岛素抵抗和动脉粥样硬化，还与血压升高有关。我们检验了这样一个假设，即 FABP4 在高血压发展的发病机制中发挥作用，包括血管平滑肌细胞（SMCs）的增殖、迁移和炎症，以及收缩反应。FABP4 本身对大鼠肠系膜动脉 SMC 的增殖、迁移和炎症没有影响，但它显著增强了去甲肾上腺素（NA）诱导的平滑肌收缩和收缩压（SBP）升高。FABP4 抑制剂 BMS-309403 通过抑制 p38 和 HSP27 的激活，显著抑制血小板衍生生长因子-BB 诱导的 DNA 合成和迁移。此外，BMS-309403 通过抑制 NF-κB 激活，显著抑制肿瘤坏死因子-α诱导的血管细胞黏附分子-1 和单核细胞趋化蛋白-1 的表达以及单核细胞黏附。有趣的是，SMC 不表达 FABP4。BMS-309403 长期治疗自发性高血压大鼠（SHR），显著抑制了分离的肠系膜动脉和左心室肥厚的舒张功能障碍，而对 SBP 没有影响。我们首次表明，FABP4 可急性增强 NA 诱导的 SBP 升高，可能是通过增强外周动脉收缩性。BMS-309403 可预防 SMC 的增殖、迁移和炎症反应，尽管外源性应用 FABP4 对细胞反应没有影响。此外，我们证明了 BMS-309403 长期治疗可部分改善 SHR 的病理状况。这些结果表明，BMS-309403 将有助于开发一种新的针对肥胖相关高血压和并发症的药物治疗剂。
