Abstract
Introduction: Pulmonary hypertension (PH) is a progressive, severe disease characterized by high blood pressure in the pulmonary circulation, inflammatory cells infiltration and excessive pulmonary vascular remodeling. Endothelial cell (EC) dysfunction is increasingly recognized as a precipitating event for this remodeling. Butyrate, a microbiome-derived molecule with histone deacetylation activity and present in circulating blood, has been associated with benefit in atherosclerosis and associated cardiovascular diseases. Due to a dearth of knowledge on the role of microbiome-derived molecules in PH-EC, we aimed to test whether butyrate plays a protective role in EC under PH. Results: Mice supplementation with butyrate (sodium butyrate, NaB) attenuated hypoxia-induced right ventricular (RV) pressure (43±2 to 35±3 mmHg, p<0.05) and RV hypertrophy (RV/LV+Septum= 0.43±0.008 to 0.38±0.01, p<0.05) in vivo. NaB also lowered hypoxia-induced circulating monocyte numbers and reduced gene expression of inflammatory adhesion molecule VCAM-1 in hypoxic lung-derived CD31+ ECs, as well as increased expression of ERM binding Phosphoprotein 50 (EBP50), a protein we have shown to modulate endothelial reprogramming in PH. In vitro, NaB attenuated PH-related inflammatory cytokine IL1β-induced human pulmonary arterial EC (HPAEC) migration at 48 h. Consistently, NaB also reversed IL1β-induced increase in VCAM-1 expression at the mRNA and protein level in HPAEC. Moreover, NaB rescued the expression of IL1β-induced reduction in cell surface protein integrin α3, EBP50, and Vangl2 (Van Gogh-like) protein, a member of planar cell polarity core whose downregulation has been linked to PH. Conclusions: Collectively our results demonstrate that butyrate attenuates PH potentially via protecting against myeloid cell induction and pathophysiological proinflammatory, promigratory pulmonary vascular EC activation. Butyrate may also reduce EC reprogramming through its effects on EBP50, and may promote pulmonary vascular homeostasis through Vangl2 induction. These findings support the potential for therapeutic benefits of butyrate in PH and the need for further investigation of the role of microbiome-derived metabolites in this devastating disease.
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