The development of pulmonary hypertension in the setting of fibrosing lung disorders is associated with worse prognosis. Despite the advances in the area of pulmonary hypertension, the precise molecular mechanisms underlying pulmonary hypertension in the setting of lung fibrosis remain unclear. Extracellular superoxide dismutase (EC-SOD) is the main extracellular antioxidant enzyme in the pulmonary vascular wall and has been implicated in the pathogenesis of pulmonary hypertension since mice overexpressing EC-SOD develop less severe pulmonary hypertension (PH), while lack of EC-SOD promotes vascular remodeling and PH. However, the role of EC-SOD in PH in the setting of lung fibrosing disorders is unknown, and the mechanisms controlling its expression in this setting remain to be elucidated. We hypothesize that PH in the setting of lung fibrosis is due to an imbalance between anti-oxidant genes like EC-SOD and pro-oxidant genes like NADPH oxidase 4 (NOX4), and that these derangements are regulated by epigenetic factors such as DNA methylation and histone modifications. If true, interventions targeting such changes might ameliorate PH in these disorders. This hypothesis is supported by our own observations. First, we found upregulation of Nox4 and downregulation of EC-SOD in pulmonary vascular structures after bleomycin-induced lung fibrosis. Second, we found that these genes are regulated by histone deacetylase (HDAC) inhibitors, which also attenuate reactive oxygen species levels in pulmonary cells. Third, we found evidence of DNA methylation and histone acetylation in the promoter of EC-SOD capable of influencing gene expression. Finally, we found that HDAC inhibitors reduce vascular remodeling and right ventricular systolic pressure in the model of bleomycin-induced lung fibrosis. Together, these observations suggest that epigenetic factors leading to an imbalance between EC-SOD and NOX4 expression underlie the development of PH in fibrotic lungs. This hypothesis will be tested using the following aims: 1) analyze the epigenetic modifications that control EC-SOD gene expression in pulmonary endothelial cells; 2) identify the epigenetic modifications influencing the expression of EC-SOD and NOX4 in vascular structures in animal models of lung fibrosis; 3) determine the impact of interventions designed to inhibit epigenetic regulation of EC-SOD and NOX4, and the mechanisms responsible for these effects. The proposed work will uncover novel mechanisms responsible for development of PH in fibrotic lungs. Such results will have an important positive impact, because the identified molecular mechanisms are expected to provide new targets and approaches for preventative and therapeutic interventions in PH and other cardio-vascular diseases.
Pulmonary arterial hypertension is a life-threatening disease characterized by elevated pulmonary artery pressure and pulmonary vascular resistance. This project investigates the role of epigenetic modifications in regulation of vascular antioxidant enzymes with the ultimate goal to slow down or reverse the development of pulmonary hypertension. Upon completion of the proposed research, we will have a better foundation upon which to investigate the novel therapeutic strategies to improve treatment of this debilitating disease.
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| Roman, Jesse; Zhu, Jianxin; Ritzenthaler, Jeffrey D et al. (2017) Epigenetic regulation of EC-SOD expression in aging lung fibroblasts: Role of histone acetylation. Free Radic Biol Med 112:212-223 |
| Zelko, Igor N; Zhu, Jianxin; Ritzenthaler, Jeffrey D et al. (2016) Pulmonary hypertension and vascular remodeling in mice exposed to crystalline silica. Respir Res 17:160 |
| Watson, Walter H; Burke, Tom J; Zelko, Igor N et al. (2016) Differential Regulation of the Extracellular Cysteine/Cystine Redox State (EhCySS) by Lung Fibroblasts from Young and Old Mice. Oxid Med Cell Longev 2016:1561305 |
| Zelko, Igor N; Folz, Rodney J (2015) Regulation of Oxidative Stress in Pulmonary Artery Endothelium. Modulation of Extracellular Superoxide Dismutase and NOX4 Expression Using Histone Deacetylase Class I Inhibitors. Am J Respir Cell Mol Biol 53:513-24 |
