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.

Diverse distribution of tyrosine receptor kinase B isoforms in rat multiple tissues

“…Western blotting was performed as described previously [ 27 , 28 , 33 , 34 ]. Protein lysates were obtained from mashed rat tissues using Cell Lysis Buffer (Cell Signaling Technology) containing 20 mM Tris-HCl (pH7.5), 150 mM NaCl, 1 mM Na 2 EDTA, 1 mM EGTA, 1% Triton-X, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 1 mM Na 3 VO 4 and 1 µ g/m l leupeptin supplemented with 0.1% protease inhibitor mixture (Nacalai Tesque, Kyoto, Japan) on ice.…”

Development of a humanized anti-FABP4 monoclonal antibody for treatment of breast cancer

“…Interestingly, mice treated with BMS309403 exhibited reduced symptoms of diabetes, atherosclerosis and mammary tumor growth(17, 31), suggesting that targeting FABP4 with small-molecular inhibitors might represent a promising approach for treating obesity-associated diseases. However, like many other small-molecule drug candidates, in vivo applications of the BMS309403 demonstrated off-target activities(32, 33), and severe side-effects, including suppressing cardiac contractile function(34). To eliminate the potential concerns related to small-molecule inhibitors, highly specific anti-FABP4 antibodies were developed to block the activity of circulating FABP4 in obese models(35, 36).…”

Human Omentin-1 Administration Ameliorates Hypertensive Complications without Affecting Hypertension in Spontaneously Hypertensive Rats

“…The BW, SBP, and HR were measured once a week (before injection and 3–4 and 10–11 days after injection). The tail-cuff system (Softron, Tokyo, Japan) was utilized in conscious conditions for a measurement of HR and SBP as described previously [ 26 , 27 , 28 ]. More than 10 measurements per 1 rat were performed.…”

“…The smooth muscle contractility was measured isometrically with a force-displacement transducer (Minebea Mitsumi, Nagano, Japan) and recorded as computer data by using the PowerLab system (ADInstruments, New South Wales, Australia). Each ring was hanged on two hooks under a resting tension of 0.5 g in the organ bath and repeatedly exposed to the high K + solution containing 72.7 mM KCl until the responses became stable as described previously [ 26 ]. Concentration-response curves to NA (100 pM–1 μM) or 5-HT (1 nM–3 μM) were obtained by the cumulative application.…”