Role of epigenetics in pulmonary hypertension

Abstract

A significant amount of research has been conducted to examine the pathologic processes and epigenetic mechanisms contributing to peripheral hypertension. However, few studies have been carried out to understand the vascular remodeling behind pulmonary hypertension (PH), including peripheral artery muscularization, medial hypertrophy and neointima formation in proximal arteries, and plexiform lesion formation. Similarly, research examining some of the epigenetic principles that may contribute to this vascular remodeling, such as DNA methylation and histone modification, is minimal. The understanding of these principles may be the key to developing new and more effective treatments for PH. The purpose of this review is to summarize epigenetic research conducted in the field of hypertension that could possibly be used to understand the epigenetics of PH. Possible future therapies that could be pursued using information from these studies include selective histone deacetylase inhibitors and targeted DNA methyltransferases. Both of these could potentially be used to silence proproliferative or antiapoptotic genes that lead to decreased smooth muscle cell proliferation. Epigenetics may provide a glimmer of hope for the eventual improved treatment of this highly morbid and debilitating disease.

Epigenetic targets for novel therapies of lung diseases

“…In addition to small molecule inhibitors of cell signaling pathways, microRNAs (miRNA) have become intensely studied molecular targets for novel anti-remodeling therapy (White et al, 2012). There is also emerging evidence for altered DNA methylation (Archer et al, 2010) and histone posttranslational modifications (Xu et al, 2010) in pulmonary hypertension, both of which are targets for new drug development (Saco et al, 2014). …”

The relevance of epigenetics to occlusive cerebral and peripheral arterial disease

“…Research examining epigenetic mechanisms that may contribute to vascular remodelling in response to fluid shear stress is limited [67] (Table 3). Laminar shear stress is an important modulating factor of eNOS expression in ECs and stimulates activating histone (H3 and H4) acetylation marks [68].…”

Progress in the understanding and management of pulmonary arterial hypertension

“…There is increasing evidence that inflammation and altered immunity provides a ‘second-hit’ 78 . Another ‘hit’ may occur via epigenetic mechanisms, such as DNA methylation, histone modification and the action of microRNAs 79 which in turn may be influenced by environmental factors, inflammation/infection, hormones or exposure to drugs The latest “metabolic theory” also proposes a central role for altered mitochondrial metabolism, promoting a switch away from glucose oxidation towards cytolsolic glycolysis and fatty acid oxidation (similar to cancer biology) which, in turn, sets a pro-proliferative, apoptosis-resistant phenotype 80 . There is now a race to synthesise a unifying theory to link genetic pre-disposition with inflammation and dysregulated metabolic function.…”