Effects of chrysin (5,7-dihydroxyflavone) on vascular remodeling in hypoxia-induced pulmonary hypertension in rats.

Xian-Wei Li,Xiang-Ming Wang,Jie-Ren Yang,Shu Li

doi:10.1186/s13020-015-0032-2

Abstract

BackgroundChrysin (5,7-dihydroxyflavone) inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation and arterial intima hyperplasia. This study aims to investigate the effects of chrysin on rat pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (PH).MethodsSprague–Dawley rats were continuously exposed to 10% O2 for 4 weeks to induce PH. The effect of chrysin (50 or 100 mg/kg/d, subcutaneous) on vascular remodeling was investigated in hypoxia-induced PH model. At the end of the experiments, the indexes for pulmonary vascular remodeling and right ventricle hypertrophy were measured by vascular medial wall thickness and the ratio of right ventricle to (left ventricle plus septum). The expressions of NOX4, collagen I, and collagen III were analyzed by immunohistochemistry, real-time PCR, or western blotting. The proliferation of cultured pulmonary artery smooth muscle cells (PASMCs) was determined by BrdU incorporation and flow cytometry. The levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were also determined by thiobarbituric acid reactive substances assay and 2′7′-dichlorofluorescein diacetate method.ResultsChrysin treatment for 4 weeks significantly attenuated pulmonary vascular remodeling and improved collagen accumulation and down-regulated collagen I and collagen III expressions, accompanied by downregulation of NOX4 expression in the pulmonary artery (P = 0.012 for 50 mg/kg/d, P < 0.001 for 100 mg/kg/d) and lung tissue (P = 0.026, P < 0.001). In vitro, chrysin (1, 10, and 100 μM) remarkably attenuated PASMC proliferation (P = 0.021 for 1 μM, P < 0.001 for 10 μM, and P < 0.001 for 100 μM), collagen I expression (P = 0.035, P < 0.001, and P < 0.001), and collagen III expression (P = 0.027, P < 0.001, and P < 0.001) induced by hypoxia, and these inhibitory effects of chrysin were accompanied by inhibition of NOX4 expression (P = 0.019, P < 0.001, and P < 0.001), ROS production (P = 0.038, P < 0.001, and P < 0.001), and MDA generation (P = 0.024, P < 0.001, and P < 0.001).ConclusionsThis study demonstrated that chrysin treatment in hypoxia-induced PH in rats reversed the hypoxia-induced (1) elevations of NOX4 expression, (2) productions of ROS and MDA, (3) proliferation of PASMC, and (4) accumulation of collagen.

Highlights

Chrysin (5,7-dihydroxyflavone) inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation and arterial intima hyperplasia
Chrysin treatment ameliorated homodynamic and cardiovascular remodeling Consistent with previous studies [30], 4 weeks of exposure to hypoxia induced pulmonary hypertension (PH) in rats, as shown by significant elevations in right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) compared with the normoxic rats (Figure 1A,B)
Hypoxia induced significant hypertrophy of the right ventricle (RV) and pulmonary arteries, with increases in the ratio of RV/left ventricle (LV) + S, percentage of wall thickness (WT), and proliferation of smooth muscle cells in the vascular media of small pulmonary arteries compared with the normoxia group (Figure 1C-E)

Summary

Introduction

Chrysin (5,7-dihydroxyflavone) inhibits platelet-derived growth factor-induced vascular smooth muscle cell proliferation and arterial intima hyperplasia. This study aims to investigate the effects of chrysin on rat pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (PH). Pulmonary hypertension (PH) is a syndrome in which obstructed, constricted small pulmonary arteries and increased pulmonary vascular resistance lead to right ventricular hypertrophy and failure [1]. The proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) and accumulation of extracellular matrix (ECM) components, such as collagens, are important processes in pulmonary vascular structural remodeling [4,5,6]. Current therapies for chronic PH-induced vasodilation reduce pulmonary arterial resistance (e.g., nitric oxide inhalation, stimulation of cGMP production by phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclin analogs) [7]. Oxidative stress is suggested to contribute greatly to the development of PH and antioxidant therapy might be a novel strategy for PH [8,9].

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