Hypoxic pulmonary arterial hypertension is characterized by elevated pulmonary vascular resistance and remodelling. Transforming growth factor-β1 (TGF-β1 ) is the master regulator in cellular response to hypoxia which can directly target lysyl oxidase (LOX). This study aimed to determine whether hypercapnia attenuates hypoxic pulmonary hypertension via regulating TGF-β1 and LOX signalling. We found that exposure to hypercapnia ameliorated the increase in mean pulmonary artery pressure (mPAP) and ratio of right ventricle to left ventricle plus septum (RV/(LV + S)) induced by hypoxia but had no effect on mPAP and RV/(LV + S) in normoxia-exposed control. In addition, exposure to hypoxia upregulated the mRNA and protein levels of LOX and TGF-β1 in rat PASMCs both in vivo and in vitro, but these effects were abrogated by concurrent exposure to hypercapnia. The downregulation of LOX in rat PASMCs induced by hypercapnia was reversed by the administration with TGF-β1 , while TGF-β1 knockdown repressed the upregulation of LOX in hypoxia-exposed rat PASMCs. In conclusion, hypoxia upregulates LOX and TGF-β1 expression in PASMCs and contributes to pulmonary hypertension. Hypercapnia downregulates hypoxia-induced LOX expression and alleviates hypoxia-associated pulmonary hypertension via inhibiting TGF-β1 signalling. SIGNIFICANCE OF THE STUDY: Hypoxia-induced upregulation of TGF-β1 , PDGF, and HIF-1α plays a pivotal role in PAH, but molecular mechanism of how hypoxia regulates LOX expression is not clear. In the present study, we showed that mRNA and protein expression levels of LOX were substantially increased when TGF-β1 was induced by hypoxia, and the effects were reversed by TGF-β1 knockdown. Our study indicates that TGF-β1 is implicated in the regulation of LOX.
Keywords: hypercapnia; hypoxia; lysyl oxidase; pulmonary hypertension; transforming growth factor-β1.
© 2019 John Wiley & Sons, Ltd.