Fucoxanthin ameliorates vascular remodeling via attenuating oxidative stress in hypoxic pulmonary hypertension rats

Hypoxic pulmonary hypertension (HPH) is a fatal cardiopulmonary disease characterized by pulmonary vascular remodeling, primarily resulting from abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs). Fucoxanthin, a natural carotenoid with potent antioxidant activity, was investigated for its therapeutic potential in HPH, given the critical role of oxidative stress in disease pathogenesis. In this study, Sprague-Dawley rats were exposed to intermittent chronic hypoxia for 4 weeks to mimic severe HPH. The results demonstrated that fucoxanthin significantly reduced the elevated right ventricular systolic pressure (RVSP), alleviated right ventricular hypertrophy, and mitigated pulmonary artery remodeling in the HPH rats. Additionally, fucoxanthin enhanced superoxide dismutase (SOD) activity and glutathione (GSH)/glutathione disulfide (GSSG) ratio while decreasing malondialdehyde (MDA) levels in both lung tissues and serum of HPH rats. In vitro, fucoxanthin inhibited cell proliferation and migration, decreased reactive oxygen species (ROS) production in hypoxia-induced PASMCs, and improved cell viability in hypoxia-induced endothelial cells (ECs). Importantly, fucoxanthin reduced hypoxia-inducible factor 1 alpha (HIF-1α) expression in both lung tissues and PASMCs under hypoxia. Notably, fucoxanthin exhibited effects similar to those of 2-methoxyestradiol (2ME2), an inhibitor of HIF-1α, on cell proliferation and ROS production in hypoxia-induced PASMCs. Moreover, fucoxanthin treatment did not significantly alter HIF-1α expression, cell proliferation, or ROS production after 2ME2 blocked HIF-1α. Collectively, fucoxanthin suppressed hypoxia-induced oxidative stress primarily by regulating the HIF-1α-ROS pathway, thereby alleviating pulmonary remodeling in HPH. Our findings represent a promising therapeutic strategy for HPH by improving pulmonary vascular remodeling.