Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Department of Cardiology, The affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China.
J Cell Physiol. 2019 Aug;234(10):17482-17493. doi: 10.1002/jcp.28370. Epub 2019 Feb 20.
Hypoxia-induced excessive pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in the pathology of pulmonary arterial hypertension (PAH). Berberine (BBR) is reported as an effective antiproliferative properties applied in clinical. However, the effect of BBR on PAH remains unclear. In the present study, we elucidated the protective effects of BBR against abnormal PASMC proliferation and vascular remodeling in chronic hypoxia-induced hearts. Furthermore, the potential mechanisms of BBR were investigated. For this purpose, C57/BL6 mice were exposed to chronic hypoxia for 4 weeks to mimic severe PAH. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased the right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum RV/(LV + S) weight ratio, and the median width of pulmonary arterioles. BBR attenuated the elevations in RVSP and RV/(LV + S) and mitigated pulmonary vascular structure remodeling. BBR also suppressed the hypoxia-induced increases in the expression of proliferating cell nuclear antigen (PCNA) and of α-smooth muscle actin. Furthermore, administration of BBR significantly increased the expression of bone morphogenetic protein type II receptor (BMPR-II) and its downstream molecules P-smad1/5 and decreased the expression of transforming growth factor-β (TGF-β) and its downstream molecules P-smad2/3. Moreover, peroxisome proliferator-activated receptor γ expression was significantly decreased in the hypoxia group, and this decrease was reversed by BBR treatment. Our study demonstrated that the protective effect of BBR against hypoxia-induced PAH in a mouse model may be achieved through altered BMPR-II and TGF-β signaling.
低氧诱导的肺动脉平滑肌细胞（PASMC）过度增殖在肺动脉高压（PAH）的病理中起重要作用。黄连素（BBR）被报道具有有效的抗增殖特性，已应用于临床。然而，BBR 对 PAH 的影响尚不清楚。在本研究中，我们阐明了 BBR 对慢性低氧诱导的心脏中异常 PASMC 增殖和血管重构的保护作用。此外，还研究了 BBR 的潜在机制。为此，将 C57/BL6 小鼠暴露于慢性低氧中 4 周以模拟严重的 PAH。血流动力学和肺病理形态学数据显示，慢性低氧显著增加了右心室收缩压（RVSP）、右心室/左心室加室间隔（RV/（LV+S））重量比和中肺动脉的中值宽度。BBR 减弱了 RVSP 和 RV/（LV+S）的升高，并减轻了肺血管结构重塑。BBR 还抑制了缺氧诱导的增殖细胞核抗原（PCNA）和α-平滑肌肌动蛋白表达的增加。此外，BBR 的给药显著增加了骨形态发生蛋白 II 型受体（BMPR-II）及其下游分子 P-smad1/5 的表达，并降低了转化生长因子-β（TGF-β）及其下游分子 P-smad2/3 的表达。此外，缺氧组中过氧化物酶体增殖物激活受体 γ的表达显著降低，BBR 治疗可逆转这种降低。我们的研究表明，BBR 对缺氧诱导的 PAH 小鼠模型的保护作用可能是通过改变 BMPR-II 和 TGF-β 信号通路实现的。
