4-Terpineol attenuates pulmonary vascular remodeling via suppressing PI3K/Akt signaling pathway in hypoxia-induced pulmonary hypertension rats

• Published in: Toxicology and applied pharmacology 2023-08, Vol.473, p.116596-116596, Article 116596
• Main Authors: Gu, Cunlin, Yang, Zhanting, Su, Shanshan, Ma, Ke, Nan, Xingmei, Li, Zhanqiang, Lu, Dianxiang
• Format: Article
• Language: English
• Subjects: 4-Terpineol; Animals; Anti-proliferation; Cell Proliferation; Glycogen Synthase Kinase 3 beta - metabolism; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - prevention & control; Hypoxia - complications; Hypoxia - drug therapy; Hypoxia - metabolism; Hypoxia-induced pulmonary hypertension; Male; Myocytes, Smooth Muscle; Oils, Volatile - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary Artery; Pulmonary vascular remodeling; Rats; Rats, Sprague-Dawley; Signal Transduction; Vascular Remodeling
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2023.116596

The hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) plays a pivotal role in pulmonary arterial remodeling (PAR) of hypoxia-induced pulmonary hypertension (HPH). 4-Terpineol is a constituent of Myristic fragrant volatile oil in Santan Sumtang. Our previous study found that Myristic fragrant volatile oil alleviated PAR in HPH rats. However, the effect and pharmacological mechanism of 4-terpineol in HPH rats remain unexplored. Male Sprague-Dawley rats were exposed to hypobaric hypoxia chamber (simulated altitudes of 4500 m) for 4 weeks to establish an HPH model in this study. During this period, rats were intragastrically administrated with 4-terpineol or sildenafil. After that, hemodynamic indexes and histopathological changes were assessed. Moreover, a hypoxia-induced cellular proliferative model was established by exposing PASMCs to 3% O2. PASMCs were pretreated with 4-terpineol or LY294002 to explore whether 4-terpineol targeted PI3K/Akt signaling pathway. The PI3K/Akt-related proteins expression was also accessed in lung tissues of HPH rats. We found that 4-terpineol attenuated mPAP and PAR in HPH rats. Then, cellular experiments showed 4-terpineol inhibited hypoxia-induced PASMCs proliferation via down-regulating PI3K/Akt expression. Furthermore, 4-terpineol decreased the p-Akt, p-p38, and p-GSK-3β protein expression, as well as reduced the PCNA, CDK4, Bcl-2 and Cyclin D1 protein levels, while increasing levels of cleaved caspase 3, Bax, and p27kip1in lung tissues of HPH rats. Our results suggested that 4-terpineol mitigated PAR in HPH rats by inhibiting the proliferation and inducing apoptosis of PASMCs through suppression of the PI3K/Akt-related signaling pathway. [Display omitted] •4-Terpineol alleviated pulmonary artery remodeling in HPH rats.•4-Terpineol repressed hypoxia-induced proliferation in PASMCs.•4-Terpineol exerted protective effects through the PI3K/Akt signaling pathway.