The emerging role of epigenetics in pulmonary arterial hypertension: an important avenue for clinical trials (2015 Grover Conference Series)

Abstract

Epigenetics is an emerging field of research and clinical trials in cancer therapy that also has applications for pulmonary arterial hypertension (PAH), as there is evidence that epigenetic control of gene expression plays a significant role in PAH. The three types of epigenetic modification include DNA methylation, histone modification, and RNA interference. All three have been shown to be involved in the development of PAH. Currently, the enzymes that perform these modifications are the primary targets of neoplastic therapy. These targets are starting to be explored for therapies in PAH, mostly in animal models. In this review we summarize the basics of each type of epigenetic modification and the known sites and molecules involved in PAH, as well as current targets and prospects for clinical trials.

Keywords: DNA methylation; histone modification; microRNA; oxidative stress; superoxide dismutase 2.

Figure 1

Mechanisms of epigenetic modification: schematic of epigenetic mechanisms. Histone modification, DNA methylation, and microRNA-mediated gene silencing constitute three mechanisms of epigenetic regulation. Acetyl CoA: acetyl coenzyme A; mRNA: messenger RNA.

Figure 2

ABT-888 (a PARP-1 inhibitor) in PAH-PASMC restores the miRNA-204/NFAT/HIF-1α axis. A, miRNA-204 levels were measured in control cells (n = 5) and PAH cells (n = 4) with or without ABT-888 (10 mmol/L for 48 hours). PARP-1 inhibition increases miRNA-204 levels, as compared to those seen in control cells. B, PARP-1 inhibition decreases NFATc2 activation, measured by nuclear translocation assay (n = 4–5). C, The same phenotype is also observed for HIF-1α, as its activation is increased in PAH PASMC and decreased upon PARP-1 inhibition (n = 4). D, PARP-1 effects are mediated by miR-204/NFAT/HIF-1α, as adding ABT-888 to another treatment (miR-204 mimic, VIVIT, siHIF-1α) does not change Ca²⁺ or ΔΨ_m (for all the experiments: n = 50 cells/experiment in 3 or 4 experiments). *P < 0.05; **P < 0.01; ***P < 0.001; triple symbols in D also indicate P < 0.001; see key for detials. FU: fluorescent units; HIF-1α: hypoxia-inducible factor 1-alpha; miR: microRNA; NFAT: nuclear factor of activated T cell; PAH: pulmonary arterial hypertension; PARP-1: poly (ADP-ribose) polymerase 1; PASMC: pulmonary arterial smooth muscle cells; si: small interfering RNA. From Meloche et al.; used with permission.

Figure 3

Western blots of right ventricular (RV) whole-cell lysates (A, B; note different order of experimental conditions compared with densitometries) show an increased protein expression of cleaved caspase-3 (densitometry in C) and collagen-I A1 (ColIA1; densitometry in E) and a decreased protein expression of vascular endothelial growth factor (VEGF; densitometry in D) and angiopoietin 1 (Angpt-1 [in B]/Ang-1; densitometry in F) in trichostatin A (TSA)–treated rats with pulmonary artery banding (PAB). Quantitative polymerase chain reaction does not show changes in VEGF gene expression in any of the experimental conditions (G), whereas Ang-1 messenger RNA (mRNA) expression is reduced by PAB and TSA, alone or in combination (H).