Abstract
Arterial wall remodeling underlies increased pulmonary vascular resistance and right heart failure in pulmonary arterial hypertension (PAH). None of the established vasodilator drug therapies for PAH prevents or reverse established arterial wall thickening, stiffening, and hypercontractility. Therefore, new approaches are needed to achieve long-acting prevention and reversal of occlusive pulmonary vascular remodeling. Several promising new drug classes are emerging from a better understanding of pulmonary vascular gene expression programs. In this review, potential epigenetic targets for small molecules and oligonucleotides will be described. Most are in preclinical studies aimed at modifying the growth of vascular wall cells in vitro or normalizing vascular remodeling in PAH animal models. Initial success with lung-directed delivery of oligonucleotides targeting microRNAs suggests other epigenetic mechanisms might also be suitable drug targets. Those targets include DNA methylation, proteins of the chromatin remodeling machinery, and long noncoding RNAs, all of which act as epigenetic regulators of vascular wall structure and function. The progress in testing small molecules and oligonucleotide-based drugs in PAH models is summarized.
Highlights
The set of proteins expressed and the abundance of proteins in cells of the vascular wall is a complex function of transcription, translation, and regulation of protein lifespan
This seems likely given that a genome-wide association study (GWAS) of systemic hypertension found several loci where DNA methylation patterns were associated with hypertension [27]
It is known that histone acetyltransferase activity is higher in lung tissue of pulmonary arterial hypertension (PAH) patients [40], but it is less clear that increased histone acetylation promotes inflammation, proliferation, cell migration, or cell survival in the arterial wall
Summary
The set of proteins expressed and the abundance of proteins in cells of the vascular wall is a complex function of transcription, translation, and regulation of protein lifespan. The therapeutic inflammatory and structural cells of the to vascular wallprevent contribute to remodeling pulmonary goal is to modify gene expression programs reverse and occlusive lesions. PAH has and developed, often after onset of epigenetic eventstherapy will prevent progression allow vascular wallseveral repair,years of favoring a symptoms This vascular means new drugs Drug must therapy reverse vascular remodeling become clinically useful. DNA, which are not routinely opportunities that are [11] This will describe recent progress in preclinical correctable in amolecule clinical setting, remarkable advances in gene editingontechnology have studies of small and oligonucleotide modifiers with the goal of focusing new therapeutic created newthat opportunities are advancing [11]. In preclinical studies of small molecule and oligonucleotide modifiers with the goal of focusing on
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