Fu Minyi, Luo Fangmei, Wang Eli, Jiang Yueping, Liu Shao, Peng Jun, Liu Bin
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Institute for Rational and Safe Medication Practices, Central South University, Changsha, China.
Front Pharmacol. 2021 Oct 26;12:755077. doi: 10.3389/fphar.2021.755077. eCollection 2021.
Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6', 7, 12-tetramethoxy-2,2'-dimethyl-1-β-berbaman, C18H18O2) is a compound isolated from . It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. , male Sprague Dawley rats were exposed to 10% O for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. , the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.
右心室重构是肺动脉高压（PAH）的重要病理特征之一。右心室肥厚或纤维化是右心室重构的主要原因。厚朴酚（6,6',7,12 - 四甲氧基 - 2,2'- 二甲基 - 1-β - 小檗胺，C18H18O2）是从……中分离出的一种化合物。它具有多种药理活性，如抗氧化和抗炎作用。本研究旨在评估厚朴酚对缺氧诱导的PAH右心室重构的影响及其潜在机制。首先，将雄性Sprague Dawley大鼠暴露于10%氧气环境中4周以建立右心室重构模型，该模型表现出肥厚和纤维化特征（Fulton指数、细胞大小、肥厚和纤维化标志物表达增加），同时伴有JAK2和STAT3磷酸化水平升高；用厚朴酚治疗可减轻这些变化。其次，将培养的H9c2细胞或心脏成纤维细胞暴露于3%氧气环境中48小时以诱导肥厚或纤维化，它们表现出肥厚（细胞大小以及心房钠尿肽和脑钠肽表达增加）或纤维化特征（Ⅰ型胶原、Ⅲ型胶原和α - 平滑肌肌动蛋白表达增加）。给予厚朴酚以及TG - 101348或JSI - 124（均为JAK2选择性抑制剂）可预防心肌肥厚和纤维化，同时伴有JAK2和STAT3磷酸化水平降低。基于这些观察结果，我们得出结论，厚朴酚可通过抑制JAK2/STAT3信号通路减轻缺氧诱导的PAH大鼠右心室肥厚和纤维化。厚朴酚可能对PAH治疗具有潜在的临床价值。
