Wang Jie, Zhang Yu, Liu Junjun, Jiang Fan, Cui Xiaopei, Lu Weida
Department of Geriatric Medicine and Laboratory of Gerontology and Anti-Aging Research, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Jinan Clinical Research Center for Geriatric Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Front Pharmacol. 2025 Jun 25;16:1621700. doi: 10.3389/fphar.2025.1621700. eCollection 2025.
The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be elucidated. This study investigated the effects of PTE on monocrotaline (MCT)-induced PAH in rats and explored the underlying molecular mechanisms in human primary pulmonary arterial endothelial cells (hPAECs) .
Experimental PAH was established by subcutaneous injection of MCT (50 mg/kg) in Sprague-Dawley rats, which were then randomly divided into vehicle or PTE (15 mg/kg via gavage) treatment groups. Endothelial-to-mesenchymal transition (EndMT) was modeled in hPAECs by treating with transforming growth factor-β, tumor necrosis factor-α, and interleukin-1β in combination.
In rats with MCT-induced PAH, administration of PTE resulted in a reduction in right ventricular systolic pressure, thereby alleviating right ventricular hypertrophy. This was accompanied by mitigation of the remodeling of pulmonary arteries. , genome-wide mRNA sequencing identified that PTE significantly downregulated the expression of high mobility group AT-hook 2 (HMGA2), a transcription factor involved in the pathogenesis of EndMT. Further, we demonstrated that PTE attenuated EndMT-related changes, including (1) reduced expression of the endothelial cell-specific markers platelet and endothelial cell adhesion molecule 1, and von Willebrand factor; (2) reduced nitric oxide production; and (3) increased expression of smooth muscle α-actin and other pro-fibrotic genes. Finally, we confirmed that PTE treatment reduced the expression of HMGA1/2 and Snai1/2 (markers of EndMT), and restored the expression of von Willebrand factor in the lungs of PAH rats.
PTE mitigates MCT-induced PAH and vascular remodeling in rats, at least in part, by inhibiting HMGA-mediated EndMT, suggesting that PTE may be a useful complementary medicine in the treatment of PAH.
天然化合物紫檀芪（PTE）具有多种心血管保护作用。然而，其对肺动脉高压（PAH）相关血管重塑的影响仍有待阐明。本研究调查了PTE对大鼠野百合碱（MCT）诱导的PAH的影响，并探讨了人原代肺动脉内皮细胞（hPAECs）中的潜在分子机制。
通过皮下注射MCT（50mg/kg）在Sprague-Dawley大鼠中建立实验性PAH，然后将其随机分为载体或PTE（通过灌胃给予15mg/kg）治疗组。通过联合用转化生长因子-β、肿瘤坏死因子-α和白细胞介素-1β处理在hPAECs中模拟内皮-间充质转化（EndMT）。
在MCT诱导的PAH大鼠中，给予PTE导致右心室收缩压降低，从而减轻右心室肥大。这伴随着肺动脉重塑的减轻。全基因组mRNA测序确定PTE显著下调高迁移率族AT钩2（HMGA2）的表达，HMGA2是一种参与EndMT发病机制的转录因子。此外，我们证明PTE减轻了EndMT相关的变化，包括：（1）内皮细胞特异性标志物血小板和内皮细胞黏附分子1以及血管性血友病因子的表达降低；（2）一氧化氮产生减少；（3）平滑肌α-肌动蛋白和其他促纤维化基因的表达增加。最后，我们证实PTE治疗降低了PAH大鼠肺中HMGA1/2和Snai1/2（EndMT标志物）的表达，并恢复了血管性血友病因子的表达。
PTE至少部分通过抑制HMGA介导的EndMT减轻MCT诱导的大鼠PAH和血管重塑，表明PTE可能是治疗PAH的一种有用辅助药物。
