Dihydroartemisinin Attenuates Pulmonary Hypertension Through Inhibition of Pulmonary Vascular Remodeling in Rats.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a malignant disease characterized by pulmonary arterial remodeling because of the abnormal proliferation and migration of pulmonary arterial smooth muscle cells. Dihydroartemisinin (DHA), an artemisinin derivative used to treat malaria, is able to inhibit fibrosis, neovascularization, and tumor proliferation. In this study, we hypothesized that DHA can be beneficial in treating PAH. To test this hypothesis, a rat model of pulmonary hypertension induced with monocrotaline (MCT) was used. Compared with MCT treatment alone, treatment with 50 or 100 mg/kg DHA significantly reduced the mean pulmonary arterial pressure (30.11 ± 2.48 mm Hg vs. 21.35 ± 3.04 mm Hg and 19.18 ± 1.98 mm Hg, respectively, both P < 0.01), right ventricular transverse diameter (4.36 ± 0.41 mm vs. 3.72 ± 0.24 mm and 3.67 ± 0.27 mm, respectively, both P < 0.01), pulmonary artery medial wall thickness (57.93 ± 11.14% vs. 34.45 ± 4.39% and 25.01 ± 6.66%, respectively, both P < 0.01), and increased tricuspid annular plane systolic excursion (1.34 ± 0.17 mm vs. 1.62 ± 0.3 mm and 1.62 ± 0.16 mm, respectively, both P < 0.05). We also found that DHA inhibited platelet-derived growth factor-BB-mediated pulmonary arterial smooth muscle cells proliferation and migration in a dose-dependent manner. Moreover, DHA downregulated ß-catenin levels while upregulating the levels of axis inhibition protein 2 (Axin2) and glycogen synthase kinase 3ß (GSK-3ß). Our findings suggest that DHA, which may be a potential candidate for PAH therapy, attenuates experimental pulmonary hypertension possibly by inhibiting pulmonary vascular remodeling.