Transcription factors in the pathogenesis of pulmonary arterial hypertension-Current knowledge and therapeutic potential

Abstract

Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure. Mortality remains high in severe cases despite significant advances in management and pharmacotherapy. Since currently approved PAH therapies are unable to significantly reverse pathological vessel remodeling, novel disease-modifying, targeted therapeutics are needed. Pathogenetically, PAH is characterized by vessel wall cell dysfunction with consecutive remodeling of the pulmonary vasculature and the right heart. Transcription factors (TFs) regulate the process of transcribing DNA into RNA and, in the pulmonary circulation, control the response of pulmonary vascular cells to macro- and microenvironmental stimuli. Often, TFs form complex protein interaction networks with other TFs or co-factors to allow for fine-tuning of gene expression. Therefore, identification of the underlying molecular mechanisms of TF (dys-)function is essential to develop tailored modulation strategies in PAH. This current review provides a compendium-style overview of TFs and TF complexes associated with PAH pathogenesis and highlights their potential as targets for vasculoregenerative or reverse remodeling therapies.

Keywords: epigenetics; epigenetics (chromatin remodeling); pathogenesis; pulmonary hypertension (PAH); reverse remodeling; targeted therapy; transcriptomics.

FIGURE 1

Transcription factor pathways in PAEC and PASMC associated with PAH. Overview of pathogenetically relevant transcription factor (TF) pathways in (A) pulmonary arterial endothelial cells (PAEC) and (B) pulmonary arterial smooth muscle cells (PASMC) upon activation by cell membrane anchored receptor signaling or cellular stress events. Depending on the pulmonary vascular cell type TF activation mediated gene transcription elicits cell-type specific downstream responses. Blue box represents cell membrane. Ca²⁺, Calcium; IP₃, Inositol 1,4,5-trisphosphate; ET-R_A/B, Endothelin Receptor Type A and B; TGFBR1/2/3, TGF-ß receptor 1/2/3; −p, Phosphorylation.

FIGURE 2

Transcription Factor Complexes in the Pulmonary Vasculature related to PAH. Overview of most relevant TF complex pathways in the pulmonary vasculature. TF complex formation upon complex inducing microenvironmental stimuli and downstream TF complex mediated gene transcription programs are shown. Yellow box represents nucleus. Blue box represents cell membrane. Dotted ovals indicate cell membrane anchored receptors. ub, Ubiquitin residue/Ubiquitination; –p, Phosphorylation.