Epigenetic Inheritance Underlying Pulmonary Arterial Hypertension
Claudio Napoli, Giuditta Benincasa, Joseph Loscalzo, Claudio Napoli, Giuditta Benincasa, Joseph Loscalzo
Abstract
In pulmonary arterial hypertension (PAH), the Warburg effect (glycolytic shift) and mitochondrial fission are determinants of phenotype alterations characteristic of the disease, such as proliferation, apoptosis resistance, migration, endothelial-mesenchymal transition, and extracellular matrix stiffness. Current therapies, focusing largely on vasodilation and antithrombotic protection, do not restore these aberrant phenotypes suggesting that additional pathways need be targeted. The multifactorial nature of PAH suggests epigenetic changes as potential determinants of vascular remodeling. Transgenerational epigenetic changes induced by hypoxia can result in permanent changes early in fetal development increasing PAH risk in adulthood. Unlike genetic mutations, epigenetic changes are pharmacologically reversible, making them an attractive target as therapeutic strategies for PAH. This review offers a landscape of the most current clinical, epigenetic-sensitive changes contributing to PAH vascular remodeling both in early and later life, with a focus on a network medicine strategy. Furthermore, we discuss the importance of the application (from morphogenesis to disease onset) of molecular network-based algorithms to dissect PAH molecular pathobiology. Additionally, we suggest an integrated network-based program for clinical disease gene discovery that may reveal novel biomarkers and novel disease targets, thus offering a truly innovative path toward redefining and treating PAH, as well as facilitating the trajectory of a comprehensive precision medicine approach to PAH.
Keywords: apoptosis; biomarkers; hypoxia; mutation; primary prevention.
Conflict of interest statement
Disclosures: The authors declare there are no conflicts of interest.
Figures
![Figure 1:. Hallmarks of PAH pathobiology.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6436974/bin/nihms-1519853-f0001.jpg)
![Figure 2:. Basic epigenetic mechanisms.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6436974/bin/nihms-1519853-f0002.jpg)
![Figure 3:. The role of epigenetic memory…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6436974/bin/nihms-1519853-f0003.jpg)
![Figure 4:. A systems biology approach: from…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6436974/bin/nihms-1519853-f0004.jpg)
![Figure 5:. Primary prevention of PAH through…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6436974/bin/nihms-1519853-f0005.jpg)
![Figure 6:. An integrated clinical program for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6436974/bin/nihms-1519853-f0006.jpg)
Source: PubMed