Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 bancho 35-1, Towada, Aomori, 034-8628, Japan.
Pflugers Arch. 2017 Nov;469(11):1425-1432. doi: 10.1007/s00424-017-2043-6. Epub 2017 Aug 3.
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)-1β (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-1β-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.
内脏脂肪组织来源的丝氨酸蛋白酶抑制剂（vaspin）是一种新发现的脂肪细胞因子，可抑制血管细胞的炎症、迁移和凋亡。我们最近的研究表明，慢性给予 vaspin 可部分预防自发性高血压大鼠的全身性高血压，其机制与抑制血管壁炎症和重构有关。肺动脉高压（PAH）是由 PA 重构、收缩功能障碍和炎症反应引起的。我们在动物模型中检验了 vaspin 能否预防 PAH 发展的假说。通过单次腹腔注射野百合碱（MCT；60mg/kg）诱导 PAH，在 MCT 注射后第 14 天开始每天给予 vaspin（1μg/kg）治疗 14 天。测量肺动脉压和离体肺内动脉（IPA）的收缩反应性。使用离体肺组织，检测 IPA 壁厚度和纤维化、基质金属蛋白酶（MMP）活性和活性氧（ROS）生成。在体外研究中，在 vaspin（5ng/ml，30min）存在下，用白细胞介素（IL）-1β（10ng/ml，48h）刺激大鼠肺动脉平滑肌细胞（PASMCs）后，检测 MMP 活性和 ROS 生成。Vaspin 显著减轻 MCT 诱导的肺动脉压升高，而对 IPA 松弛功能障碍没有影响。Vaspin 显著预防 MCT 诱导的 IPA 纤维化，但不预防肥大。Vaspin 显著抑制 MCT 诱导的肺组织 ROS 生成和 MMP-2 激活。此外，vaspin 显著抑制 IL-1β诱导的 PASMCs 中 ROS 生成和 MMP-2 激活。总之，我们首次证明 vaspin 通过抑制 ROS/MMP-2/纤维化通路至少部分预防 MCT 诱导的 PAH。
