Chronic intermittent hypoxia exacerbates cardiac dysfunction by impairing lymphatic function through the downregulation of S1P production and transport
L Runqian, F Yu, F Zhou, P Zhen, S Song, Z Liu, S Li, M Zhou, Q Wei, J TongAbstract
Background
The cardiac lymphatic system plays a crucial role in regulating cardiac fluid balance and maintaining cardiac homeostasis. Chronic intermittent hypoxia (CIH), a hallmark of sleep-disordered breathing (SDB), contributes to the progression of heart failure. However, the impact of CIH on the cardiac lymphatic system and the underlying mechanisms remains unclear.
Methods
In vivo studies included echocardiography, pathological tissue staining, and immunofluorescence labeling to assess the effects of SPNS2 gene knockout on cardiac lymphatic system function and lymphangiogenesis. Evans blue staining was used to detect lymphatic vessel damage in the whole heart. We investigated the expression of Sphk1, Sphk2, SPNS2, and the intracellular signaling molecule cAMP, as well as the expression of lymphatic endothelial cell markers LYVE-1, Podoplanin, and PROX-1. In vitro studies utilized Transwell migration assays, CCK-8 assay, TUNEL assay, and tube formation experiments to evaluate cell migration, viability, apoptosis, and angiogenesis in human lymphatic endothelial cells under CIH, S1P, and SPNS2 manipulation conditions.
Results
CIH significantly compromises the reparative capacity of lymphatic endothelial cells (LECs), leading to reduced proliferation, angiogenesis, and migration, alongside increased ROS accumulation and apoptosis. These effects are associated with diminished production of S1P-synthesizing enzymes (SPHK1, SPHK2) and the S1P transporter (SPNS2), as well as reduced S1P1 activation. Exogenous S1P administration partially reversed these detrimental effects, promoting lymphatic vessel function and enhancing endothelial cell viability. Under CIH conditions, overexpression of SPNS2 augmented LEC function, whereas SPNS2 knockdown impaired these functions and altered intracellular/extracellular S1P levels. Collectively, this study demonstrates that CIH-affected S1P production and transport are involved in the regulation of lymphangiogenesis via the S1P1.
Conclusions
HF progression is promoted by CIH through the disruption of cardiac lymphatic function, mediated by impaired S1P production and transport in cardiac lymphatic endothelial cells.Graphic abstractS1P rescues SPNS2 knockdown in LECs.