Additional pathogenic pathways and potential therapeutic targets in pulmonary arterial hypertension (PAH)

PathwayRole in PAHPotential therapeutic targetsRefs
Transcription factorsFoxO1, a member of the Forkhead box O (FoxO) family of transcription factors that are key regulators of cellular proliferation, is downregulated in pulmonary vessels/PASMCs of human/experimental PH lungs
Activation of the prosurvival transcription factors STAT3, NFAT, and HIF-1α has been demonstrated in experimental models of PAH
[28, 82, 83]
NOTCH3-HES5 signallingNOTCH3 is overexpressed in small PASMCs in human PH
There is evidence for a link between NOTCH3 receptor signalling through HES5 and SMC proliferation in the development of PAH
NOTCH3-HES5 pathway[84]
Epigenetic mechanismsMethylation-induced downregulation of SOD2 in PASMCs may create a metabolic state that favours proliferation and suppresses apoptosis
Aberrant expression of HDACs and BRD4 (a transcriptional regulator that recognises acetylated lysine residues) is consistent with altered epigenetic mechanisms in PAH
Studies have shown that miRNAs (small RNA molecules that negatively regulate expression of target genes) are dysregulated in patients with PAH
DNA damage/
PARP-1 signalling pathway
Activation of PARP-1 (a DNA repair enzyme) may lead to subsequent activation of transcription factors (NFAT, HIF-1α) that are implicated in PAH
Inflammation induces DNA damage in PASMCs (levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells), which may lead to activation of PARP-1 in PAH
DNA damage/PARP-1 signalling pathway[82, 89]
VEGFR signallingVEGF plasma levels are elevated in patients with severe PAH, and expression of VEGF and VEGFR2 is robust in complex vascular lesions of PAH lungs
Role of VEGF in mechanisms of PAH development is not clear
VEGFR signalling[90]

HES5: hairy and enhancer of split 5; PARP-1: Poly [ADP-ribose] polymerase 1; VEGFR: vascular endothelial growth factor receptor; PASMCs: pulmonary artery smooth muscle cells; PH: pulmonary hypertension; STAT3: Signal transducer and activator of transcription 3; NFAT: nuclear factor of activated T-cells; HIF-1α: hypoxia-inducible factor-1α; PIM1: proto-oncogene serine/threonine-protein kinase; SMC: smooth muscle cell; SOD2: superoxide dismutase 2; HDACs: histone deacetylases; BRD4: bromodomain-containing protein 4; miRNAs: microRNAs; VEGF: vascular endothelial growth factor.