Mechanisms contributing to persistently activated cell phenotypes in pulmonary hypertension

Abstract

Chronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation and extracellular matrix (ECM) remodelling. Current therapies for PH, focusing on vasodilatation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development. Although these approaches have produced a large number of compelling PH treatment targets, many promising human drugs have failed in PH clinical trials. Herein, we propose that one contributing factor to these failures is that processes important in PH development may not be good treatment targets in the established phase of chronic PH. We hypothesize that this is due to alterations of chromatin structure in PH cells, resulting in functional differences between the same factor or pathway in normal or early PH cells versus cells in chronic PH. We propose that the high expression of genes involved in the persistently activated phenotype of PH vascular cells is perpetuated by an open chromatin structure and multiple transcription factors (TFs) via the recruitment of high levels of epigenetic regulators including the histone acetylases P300/CBP, histone acetylation readers including BRDs, the Mediator complex and the positive transcription elongation factor (Abstract figure). Thus, determining how gene expression is controlled by examining chromatin structure, TFs and epigenetic regulators associated with aberrantly expressed genes in pulmonary vascular cells in chronic PH, may uncover new PH therapeutic targets.

Overview: pulmonary vascular function in health and disease

“…A review of the literature conducted by Hu et al . () supports the hypothesis that failure of treatments to reverse pulmonary hypertension may be due to persistent activation of vascular cells resulting from epigenetic changes and aberrantly expressed genes in pulmonary vascular cells in later stage pulmonary hypertension, which may differ from the gene expression profile at early stage disease. Thus, understanding the temporal course of the disease, focusing on later stages and developing appropriate pre‐clinical models are likely to be needed to uncover new therapeutic targets.…”

Suppression of HIF2 signalling attenuates the initiation of hypoxia-induced pulmonary hypertension

“…In summary, our studies have demonstrated a positive role of HIF2 in PH development in response to chronic hypoxia in normal adult animals. However, more research is needed to determine if HIF2 is truly a good PH treatment target because HIF2 activity is likely to be one of the many factors that are required, acting in different cell types, at different stages, to initiate PH (45). In addition, there are data from cancer research that factors/pathways that initiate cancer often fail to be good treatment tragets because there are many additional changes occur during cancer progression.…”

Inflammatory Basis of Pulmonary Arterial Hypertension

“…52 Therefore, tissue destruction and inflammation can continue in the absence of the initial immune stimulus. This, along with epigenetic changes in parenchymal cells, 54 may well form the basis for the chronic, progressive nature of pulmonary arterial hypertension.…”