RESUMO
Visceral adipose tissue-derived serine protease inhibitor (vaspin), a recently identified adipocytokine, inhibits inflammation, migration, and apoptosis of vascular cells. We have recently demonstrated that chronic administration of vaspin to spontaneously hypertensive rats partly prevents systemic hypertension through inhibiting inflammation and remodeling of vascular wall. Pulmonary arterial (PA) hypertension (PAH) is caused by PA remodeling, contractile dysfunction, and inflammatory responses. We tested the hypothesis that vaspin could prevent development of PAH in animal model. PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg), and vaspin (1 µg/kg/day) was treated for 14 days from the day of MCT injection. PA pressure and contractile reactivity of isolated intrapulmonary artery (IPA) were measured. Using isolated lung tissues, IPA wall thickness and fibrosis, matrix metalloproteinase (MMP) activity, and reactive oxygen species (ROS) generation were examined. For in vitro study, after rat PA smooth muscle cells (PASMCs) were stimulated with interleukin (IL)-1ß (10 ng/ml, 48 h) in the presence of vaspin (5 ng/ml, 30 min), MMP activity and ROS generation were examined. Vaspin significantly attenuated MCT-induced rise in PA pressure, while it had no influence on impairment of relaxing function in IPA. Vaspin significantly prevented MCT-induced IPA fibrosis but not hypertrophy. Vaspin significantly inhibited MCT-induced ROS generation and MMP-2 activation in lung tissues. In addition, vaspin significantly inhibited IL-1ß-induced ROS generation and MMP-2 activation in PASMCs. In summary, we for the first time demonstrate that vaspin prevents MCT-induced PAH at least in part via inhibiting ROS/MMP-2/fibrosis pathway.
Assuntos
Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Gordura Intra-Abdominal/metabolismo , Monocrotalina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Artéria Pulmonar/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
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.