Unraveling the epigenetic landscape of pulmonary arterial hypertension: implications for personalized medicine development

Abstract

Pulmonary arterial hypertension (PAH) is a multifactorial disease associated with the remodeling of pulmonary blood vessels. If left unaddressed, PAH can lead to right heart failure and even death. Multiple biological processes, such as smooth muscle proliferation, endothelial dysfunction, inflammation, and resistance to apoptosis, are associated with PAH. Increasing evidence suggests that epigenetic factors play an important role in PAH by regulating the chromatin structure and altering the expression of critical genes. For example, aberrant DNA methylation and histone modifications such as histone acetylation and methylation have been observed in patients with PAH and are linked to vascular remodeling and pulmonary vascular dysfunction. In this review article, we provide a comprehensive overview of the role of key epigenetic targets in PAH pathogenesis, including DNA methyltransferase (DNMT), ten-eleven translocation enzymes (TET), switch-independent 3A (SIN3A), enhancer of zeste homolog 2 (EZH2), histone deacetylase (HDAC), and bromodomain-containing protein 4 (BRD4). Finally, we discuss the potential of multi-omics integration to better understand the molecular signature and profile of PAH patients and how this approach can help identify personalized treatment approaches.

Keywords: Epidrugs; Epigenetic; PAH; Pulmonary arterial hypertension; Treatment.

Fig. 1

Clinical classification of pulmonary hypertension. The World Health Organization classifies PH into five groups based on its etiology, clinical presentation, hemodynamics, and characteristics. Group 1 includes pulmonary arterial hypertension (PAH), which is idiopathic, heritable, or associated with conditions such as connective tissue disease, congenital heart disease, HIV infection, or portal hypertension. Group 2 includes PH due to left heart disease. This type of PH is caused by left ventricular (LV) dysfunction or valvular disease. Group 3 includes PH due to lung diseases and/or hypoxia, such as chronic obstructive pulmonary disease, interstitial lung disease, and sleep-disordered breathing. Group 4 includes chronic thromboembolic pulmonary hypertension caused by recurrent thromboembolic occlusion of the pulmonary arteries. Group 5 includes PH with unclear and/or multifactorial mechanisms. Classification of PH is crucial for accurate diagnosis, appropriate treatment, and a better understanding of the pathophysiology of the disease. HF heart failure, LVEF left ventricular ejection fraction, mPAP mean pulmonary arterial pressure, PAH pulmonary arterial hypertension, PAWP pulmonary arterial wedge pressure, PVR pulmonary vascular resistance, and WU wood units. Created with BioRender.com

Fig. 2

Overview of the pathogenesis of PAH: triggers and cellular and biological alterations. PAH is characterized by the thickening of the pulmonary artery walls and a decrease in lumen size, leading to increased pulmonary vascular resistance and right ventricular failure. Triggers include genetic/epigenetic alterations, inflammation, infections, hypoxia, and drugs/toxins, which promote a pro-inflammatory and prothrombotic phenotype in PAEC, PASMC, and fibroblasts. This leads to vasoconstriction, cell proliferation/migration, and the inhibition of apoptosis. Media thickening also contributes to vessel narrowing. Late-stage PAH is often accompanied by decompensated RV failure, associated with capillary rarefaction, metabolic changes, oxidative stress, inflammation, fibrosis, and neurohormonal activation. LV left ventricle, PAH pulmonary arterial hypertension, RV right ventricle. Created with BioRender.com

Fig. 3

Epigenetic modifications and potential therapeutic targets for PAH. Epigenetic modifications such as DNA methylation, histone acetylation, and methylation play crucial roles in PAH. Increased HDAC activity in PAH represses the expression of genes involved in vasodilation and angiogenesis. EZH2, a histone methyltransferase enzyme that catalyzes the methylation of lysine 27 on histone H3, is also implicated in PAH pathogenesis. Furthermore, the epigenetic reader BRD4 is a transcriptional co-activator that binds to acetylated lysine residues on histone proteins and facilitates recruitment of transcriptional machinery to target genes. Additionally, DNMT1, TET1, and TET2 dysregulation induces aberrant DNA methylation patterns that contribute to the development and progression of PAH. Targeting epigenetic modifications with drugs such as BET (JQ1, apabetalone [RVX-208]), DNMT (5ʹ-aza-2ʹdeoxycytidine, decitabine), HDAC (SAHA, VPA, MGCD0103, MS-275), and EZH2 (tazemetostat, GSK126) inhibitors has shown promise as potential therapies for PAH by reversing the hyperproliferative and anti-apoptotic phenotypes of cells in the pulmonary vasculature. DNMT DNA methyltransferase, TET ten-eleven translocation methylcytosine dioxygenase, BRD4 bromodomain-containing protein 4, EZH2 enhancer of zeste homolog 2, HDAC Histone Deacetylase, H3K27me3 histone 3 lysine 27 trimethylation, Me methylation, Ac acetylation, SAHA suberoylanilide hydroxamic acid, VPA valproic acid. Created with BioRender.com

Fig. 4

Overview of the relationship between single and multi-omics. Results and data from single omics studies can be integrated into multi-Omics to provide a more comprehensive understanding of genetic changes and associated modifications in complex diseases such as PAH. Through multi-omics, there is an enhanced potential for earlier diagnosis, better treatment efficacy, and a more personalized therapy, resulting in improved patient outcomes. WGS whole genome sequencing, ChIP-seq chromatin immunoprecipitation sequencing, RNA-seq RNA sequencing, MS mass spectrometry, HPLC high performance liquid chromatography, MR mendelian randomization, NMR nuclear magnetic resonance, SNP single nucleotide polymorphism, miRNA micro-RNA, DNAm DNA methylation, TF transcription factor. Created with BioRender.com