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.
Hypoxic pulmonary hypertension (HPH) is a progressive cardiopulmonary system disease characterized by pulmonary vascular remodeling. Its occurrence and progression are closely related to oxidative stress. Lycopene, extracted from red vegetables and fruits, exhibits a particularly high antioxidant capacity that is beneficial for cardiovascular diseases. Nevertheless, the role and mechanism of lycopene in HPH remain unknown. Here, we found that lycopene reversed the elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling induced by hypoxia in rats. In vitro, lycopene caused lower proliferation and migration of PASMCs, with higher apoptosis. Consistent with the antiproliferative result of lycopene on hypoxic PASMCs, the hippo signaling pathway associated with cell growth was activated. Furthermore, lycopene reduced malondialdehyde (MDA) levels and enhanced superoxide dismutase (SOD) activity in the lungs and serum of rats under hypoxia conditions. The expression of NOX4 in the lungs was also significantly decreased. Hypoxic PASMCs subjected to lycopene showed decreased reactive oxygen species (ROS) production and NOX4 expression. Importantly, lycopene repressed HIF-1α expression both in the lungs and PASMCs in response to hypoxia in the absence of a significant change of HIF-1α mRNA. Compared with 2ME2 (a HIF-1α inhibitor) alone treatment, lycopene treatment did not significantly change PASMC proliferation, NOX4 expression, and ROS production after 2ME2 blocked HIF-1α, suggesting the inhibitory effect of lycopene on HIF-1α-NOX4-ROS axis and the targeted effect on HIF-1α. After CHX blocked protein synthesis, lycopene promoted the protein degradation of HIF-1α. MG-132, a proteasome inhibitor, notably reversed the decrease in HIF-1α protein level induced by lycopene in response to hypoxia. Therefore, lycopene suppressed hypoxia-induced oxidative stress through HIF-1α-NOX4-ROS axis, thereby alleviating HPH. Our findings will provide a new research direction for clinical HPH therapies.
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