Abstract
Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation.DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analyzed using bioinformatics tools.Unsupervised hierarchical clustering allowed the identification of two clusters of probes that discriminates controls and PAH patients. Among 147 differential methylated promoters, 46 promoters coding for proteins or miRNAs were related to lipid metabolism. Top 10 up and down-regulated genes were involved in lipid transport including ABCA1, ABCB4, ADIPOQ, miR-26A, BCL2L11. NextBio meta-analysis suggested a contribution of ABCA1 in PAH. We confirmed ABCA1 mRNA and protein downregulation specifically in PAH PEC by qPCR and immunohistochemistry and made the proof-of-concept in an experimental model of the disease that its targeting may offer novel therapeutic options.In conclusion, DNA methylation analysis identifies a set of genes mainly involved in lipid transport pathway which could be relevant to PAH pathophysiology.
Highlights
Pulmonary arterial hypertension (PAH) is a rare and severe condition defined by right heart catheterization as precapillary pulmonary hypertension, in the absence of other causes such as chronic thromboembolic pulmonary disease or chronic respiratory diseases and/or hypoxia [1]
Only three promoters were differentially methylated between idiopathic PAH (IPAH) and heritable PAH (HPAH) patients suggesting that these patients present a similar methylation profile in their pulmonary endothelial cells (PEC) despite different aetiologies (Figure 2A)
The Principal Component Analysis (PCA) analysis confirmed that methylation pattern is similar between hPAH and iPAH (Figure 2B)
Summary
Pulmonary arterial hypertension (PAH) is a rare and severe condition defined by right heart catheterization as precapillary pulmonary hypertension (mean pulmonary arterial pressure ≥ 25 mmHg and pulmonary artery wedge pressure ≤ 15 mmHg), in the absence of other causes such as chronic thromboembolic pulmonary disease or chronic respiratory diseases and/or hypoxia [1]. PAH is the consequence of the progressive narrowing of the pulmonary precapillary vasculature that increases pulmonary vascular resistance. Pulmonary endothelial cell (PEC) dysfunction is a major player of PAH pathobiology. It is characterized by 1) PEC barrier breakdown, endothelial-to-mesenchymal transition and subsequent neointima formation [2], 2) pulmonary arterial vasoconstriction and remodeling through paracrine production of potent vasoconstrictors and growth factors that induce the contraction and the proliferation of underlying pulmonary arterial smooth muscle cells (PASMC) (medial hypertrophy) [3], pulmonary vascular inflammation [4], and in situ thrombosis [5]. Approved PAH therapies are all targeting three major PEC dysfunctional pathways involved in the abnormal PEC-PASMC crosstalk [6]. None are curative, prompting the need of targeting other pathological signaling pathways in the future management of PAH
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