Abstract 15368: A Fatty-Acid Binding Protein 4 Inhibitor Prevents Proliferation, Migration and Inflammatory Responses in Vascular Smooth Muscle Cells
Backgrounds: Fatty-acid binding protein (FABP) 4 is an adipocytokine. Since blood FABP4 level is increased in hypertensive subjects, we tested the hypothesis that FABP4 controls key pathological processes for hypertension development, including proliferation, migration and inflammation of vascular smooth muscle cells (SMCs) as well as contractile reactivity.
Methods: (1) After cultured rat mesenteric arterial SMCs were stimulated with FABP4, proliferation and migration assays and Western blotting were performed. (2) Acute effects of FABP4 on contraction of rat isolated mesenteric artery were examined. (3) After SMCs were stimulated with PDGF-BB or TNF-α in the presence of BMS309403, an FABP4 inhibitor, proliferation and migration assays, Western blotting and qPCR were done. (4) Chronic effects of BMS309403 (5 mg/kg, i.p., 4 weeks) on systolic blood pressure (SBP) in SHR were examined.
Results: (1) FABP4 (100 ng/ml) alone had no influence on proliferation, migration and inflammatory states (n=5-10). (2) In contrast, FABP4 significantly augmented noradrenaline-induced smooth muscle contraction (n=10, p<0.01). (3) BMS309403 (5 μM) significantly inhibited PDGF-BB (10 ng/ml, 24 h)-induced DNA synthesis (n=4, p<0.01) and migration (n=4, p<0.01). The inhibitory mechanism was a prevention of p38 (n=8, p<0.05)/HSP27 (n=6, p<0.01) signals. BMS309403 (10 μM) significantly inhibited TNF-α (10 ng/ml, 24 h)-induced expression of VCAM-1 (n=6, p<0.05) and MCP-1 (n=4, p<0.01) as well as monocyte adhesion (n=6, p<0.05). The inhibitory mechanism was a prevention of NF-κB (n=5, p<0.05). Unexpectedly, SMCs do not express FABP4. (4) While BMS309403 had no influence on SBP (n=6), it significantly inhibited the impaired relaxing function in isolated mesenteric artery (p<0.05, n=12) and left ventricular hypertrophy (p<0.05, n=6) of SHR.
Conclusion: The present study for the first time reveals that BMS309403 has beneficial inhibitory effects on proliferation, migration and inflammation of vascular SMCs. Interestingly, the effects are independent of FABP4. Exogenous FABP4 application can enhance smooth muscle contractility but not other processes. BMS309403 would be a new pharmaco-therapeutic agent against obesity-associated hypertension.
Author Disclosures: Y. Okamura: None. A. Sekiguchi: None. T. Kogane: None. C. Kakuda: None. Y. Sakamoto: None. M. Okada: None. H. Yamawaki: None.
- © 2016 by American Heart Association, Inc.