Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, China.
Department of Pharmacology, Shanxi Medical University, Taiyuan, 030001, China.
Pulm Pharmacol Ther. 2018 Feb;48:124-135. doi: 10.1016/j.pupt.2017.11.003. Epub 2017 Nov 10.
BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder characterized by elevated pulmonary arterial pressure (PAP) and right ventricular hypertrophy (RVH) driven by progressive vascular remodeling. Reversing adverse vascular remodeling is an important concept in the treatment of PAH. Endothelial injury, inflammation, and oxidative stress are three main contributors to pulmonary vascular remodeling. Baicalein is a natural flavonoid that has been shown to possess anti-proliferative, anti-inflammatory, anti-oxidative, and cardioprotective properties. We hypothesized that baicalein may prevent the progression of PAH and preserve the right heart function by inhibiting pulmonary arterial remodeling. METHODS: Male Sprague-Dawley rats were distributed randomly into 4 groups: control, monocrotaline (MCT)-exposed, and MCT-exposed plus baicalein treated rats (50 and 100 mg/kg/day for 2 weeks). Hemodynamic changes, RVH, and lung morphological features were examined on day 28. Apoptosis was determined by TUNEL staining, and the mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 were detected by qRT-PCR. The changes in oxidative indicators, including malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured using corresponding commercial kits. The levels of Bax, Bcl-2, and cleaved caspase-3, and the activation of mitogen-activated protein kinase (MAPK) and NF-κB were assessed by western blotting. RESULTS: MCT induced an increase in hemodynamic parameters and RVH, which were attenuated by baicalein treatment. Baicalein also blocked MCT-induced pulmonary arterial remodeling. The levels of apoptotic (Bax/Bcl-2 ratio and cleaved caspase-3) and inflammatory (IL-6, TNF-α, and IL-1β) biomarkers in lung tissue were lower in baicalein-treated groups. Baicalein also decreased MDA level, and increased SOD and GSH-Px activity in rat pulmonary tissue. Furthermore, baicalein inhibited MCT-induced activation of the MAPK and NF-κB pathways. CONCLUSION: Baicalein ameliorates MCT-induced PAH by inhibiting pulmonary arterial remodeling at least partially via the MAPK and NF-κB pathways in rats.
背景：肺动脉高压（PAH）是一种破坏性的心肺疾病，其特征是肺动脉压（PAP）升高和右心室肥厚（RVH），由进行性血管重塑驱动。逆转不利的血管重塑是 PAH 治疗的一个重要概念。内皮损伤、炎症和氧化应激是肺血管重塑的三个主要因素。黄芩素是一种天然黄酮类化合物，已被证明具有抗增殖、抗炎、抗氧化和心脏保护作用。我们假设黄芩素可能通过抑制肺动脉重塑来预防 PAH 的进展并维持右心功能。
方法：雄性 Sprague-Dawley 大鼠随机分为 4 组：对照组、野百合碱（MCT）暴露组和 MCT 暴露加黄芩素治疗组（50 和 100mg/kg/天，持续 2 周）。第 28 天检测血流动力学变化、RVH 和肺形态特征。TUNEL 染色法测定细胞凋亡，qRT-PCR 检测肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的 mRNA 水平。采用相应的商业试剂盒测定丙二醛（MDA）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）等氧化指标的变化。通过 Western blot 检测 Bax、Bcl-2 和裂解的 caspase-3 的水平，以及丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB）的激活。
结果：MCT 诱导血流动力学参数和 RVH 增加，黄芩素治疗可减轻这些变化。黄芩素还阻断了 MCT 诱导的肺动脉重塑。黄芩素治疗组肺组织中凋亡（Bax/Bcl-2 比值和裂解的 caspase-3）和炎症（IL-6、TNF-α和 IL-1β）生物标志物水平降低。黄芩素还降低了大鼠肺组织中 MDA 水平，增加了 SOD 和 GSH-Px 的活性。此外，黄芩素抑制了 MCT 诱导的 MAPK 和 NF-κB 途径的激活。
结论：黄芩素通过至少部分通过 MAPK 和 NF-κB 途径抑制大鼠 MCT 诱导的 PAH 来改善 MCT 诱导的 PAH，从而抑制肺动脉重塑。
Pulm Pharmacol Ther. 2017-11-10
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