Prolyl 4‐Hydroxylase Domain Protein 3 Overexpression Improved Obstructive Sleep Apnea—Induced Cardiac Perivascular Fibrosis Partially by Suppressing Endothelial‐to‐Mesenchymal Transition

Abstract

BackgroundIntermittent hypoxia (IH) induced by obstructive sleep apnea is the key factor involved in cardiovascular fibrosis. Under persistent hypoxia condition, endothelial cells respond by endothelial‐to‐mesenchymal transition (EndMT), which is associated with cardiovascular fibrosis. Prolyl 4‐hydroxylase domain protein 3 (PHD3) is a cellular oxygen sensor and its expression increased in hypoxia. However, its role in obstructive sleep apnea–induced EndMT and cardiovascular fibrosis is still uncertain. We investigated the potential mechanism of obstructive sleep apnea–induced cardiac perivascular fibrosis and the role of PHD3 in it. Methods and ResultsIn vivo, C56BL/6 mice were exposed to IH for 12 weeks. PHD3 expression was changed by lentivirus‐mediated short‐hairpin PHD3 and lentivirus carrying PHD3 cDNA. EndMT related protein levels, histological and functional parameters were detected after 12 weeks. In vitro, human umbilical vein endothelial cells were treated with IH/short‐hairpin PHD3/lentivirus carrying PHD3 cDNA to explore the mechanism of PHD3 in altered function of human umbilical vein endothelial cells. We found that chronic intermittent hypoxia increase PHD3 expression and EndMT. In vivo, IH accelerate cardiac dysfunction and aggravate collagen deposition via the process of EndMT. And, when PHD3 were overexpressed, cardiac dysfunction and collagen excessive deposition were improved. In vitro, IH induced EndMT, which endow human umbilical vein endothelial cells spindle morphology and an enhanced ability to migration and collagen secretion. PHD3 overexpression in cultured human umbilical vein endothelial cells ameliorated IH–induced EndMT through inactivating hypoxia‐inducible factor 1 alpha and small mothers against decapentaplegic 2 and 3. ConclusionsObstructive sleep apnea–induced cardiac perivascular fibrosis is associated with EndMT, and PHD3 overexpression might be beneficial in the prevention of it by inhibiting EndMT. PHD3 overexpression might have therapeutic potential in the treatment of the disease.

Keywords

• cardiac perivascular fibrosis
• endothelial‐to‐mesenchymal transition
• intermittent hypoxia
• obstructive sleep apnea
• prolyl 4‐hydroxylase domain protein 3