Luteolin alleviates right ventricular hypertrophy in high altitude pulmonary hypertension rats by regulating PI3K/AKT/mTOR signalling pathway

Bin Hou; Shanshan Su; Lei Ji; Meiduo Huayu; Na Yang; Zhanting Yang; Zhanqiang Li; Dianxiang Lu

doi:10.1016/j.ejphar.2025.177898

Luteolin alleviates right ventricular hypertrophy in high altitude pulmonary hypertension rats by regulating PI3K/AKT/mTOR signalling pathway

Eur J Pharmacol. 2025 Jul 1:177898. doi: 10.1016/j.ejphar.2025.177898. Online ahead of print.

Authors

Bin Hou¹, Shanshan Su², Lei Ji³, Meiduo Huayu⁴, Na Yang⁴, Zhanting Yang⁴, Zhanqiang Li⁵, Dianxiang Lu⁶

Affiliations

¹ Research Center for High Altitude Medicine, Key Laboratory for High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China; Qinghai Provincial People's Hospital, Xining, 810007, China.
² Technical Center of Xining Customs, Key Laboratory of Food Safety Research in Qinghai Province, Xining, 810013, China.
³ Qinghai Provincial People's Hospital, Xining, 810007, China.
⁴ Research Center for High Altitude Medicine, Key Laboratory for High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China.
⁵ Research Center for High Altitude Medicine, Key Laboratory for High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China. Electronic address: zhanqiang_li@qhu.edu.cn.
⁶ Research Center for High Altitude Medicine, Key Laboratory for High Altitude Medicine (Ministry of Education), Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining, 810001, China; Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu, 610106, China. Electronic address: ludianxiang@126.com.

PMID: 40609617
DOI: 10.1016/j.ejphar.2025.177898

Abstract

High altitude pulmonary hypertension (HAPH) is a chronic high-altitude disease caused by chronic hypoxia. Protecting right ventricular (RV) structure and function constitutes a key strategy for improving HAPH prognosis. Luteolin, a plant-derived flavonoid with cardiovascular protective properties, has been shown to reduce pulmonary artery pressure by improving vascular remodelling in HAPH. However, its direct effects on the right ventricle remain unclear. We investigated the effect of luteolin on RV structure/function in HAPH rats and its mechanism of action using hypertrophic H9c2 cardiomyocytes. In vivo, luteolin decreased the Fulton index, RV fibrosis, and cardiomyocyte cross-sectional area, while improving the pulmonary acceleration time, pulmonary ejection time, pulmonary acceleration time/pulmonary ejection time ratio, thickness and tricuspid annular plane systolic excursion, and RV-pulmonary artery coupling. In vitro experiments demonstrated reduced surface area of angiotensin II-induced hypertrophic cardiomyocytes. Both animal and cellular experiments showed that luteolin effectively reduced hypoxia/angiotensin II-induced brain natriuretic peptide upregulation. Hypoxia/angiotensin II increased Beclin-1 and the LC3 II/LC3 I ratio and decreased p62 levels. Luteolin reversed these changes and reduced autophagy. Transmission electron microscopy and adenovirus transfection confirmed increased autolysosomes in hypoxia/angiotensin II-treated cardiomyocytes. Decreased Bcl-2 levels, increased Bax expression, and Bax/Bcl-2 ratio elevation were reversed by luteolin. Terminal deoxynucleotidyl transferase dUTP nick end labelling staining confirmed suppression of apoptosis by luteolin. Network pharmacology predicted and screened the PI3K/AKT target. Luteolin decreased PI3K, AKT, and mTOR phosphorylation, without altering total protein levels. In conclusion, luteolin restored RV structure and function in HAPH rats, reversed cardiomyocyte hypertrophy, and inhibited autophagy and apoptosis.

Keywords: Apoptosis; Autophagy; High altitude pulmonary hypertension; Luteolin; PI3K/AKT/mTOR signalling pathway; Right Ventricular Structure.