Metabolic and Epigenetic Interactions Regulate Vascular Phenotypic Change and Maintenance in Pulmonary Hypertension
Abstract
Despite recent advances in diagnosis and treatment, pulmonary hypertension (PH) remains a devastating disease with high mortality affecting both adult and pediatric patients. While it can arise for unknown (idiopathic) or genetic reasons, it is more frequently associated with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, obesity, and viral infections, disorders that are very prevalent among Veterans. A lack of understanding of the factors that cause PH in patients with chronic lung disease has limited the therapeutic options for these patients. Notable is the fact that though some progress has been made in the treatment of patients with idiopathic PAH, none of the drugs shown to be useful in these patients have shown any benefit in patients with chronic hypoxic lung diseases, such as COPD, or lung fibrosis. Pulmonary hypertension, in the aforementioned chronic lung diseases, is generally believed to be hypoxic in origin. However, PH in these patients is often irreversible or only minimally reversible with supplemental oxygen. This may be due to structural changes in the lung blood vessels in these patients. These vessels exhibit thickening and fibrotic changes due to excessive proliferation and resistance to normal senescence of resident pulmonary vascular wall cells. Recent studies also suggest that an inflammatory mechanism plays a significant role in the pathogenesis of these forms of PH. Interestingly, cells in the hypertensive lung blood vessels, including the ones we are proposing to study, endothelial cells and fibroblasts, have recently been shown to exhibit many features of cancer cells including excessive proliferation, resistance to death, and a hyperinflammatory phenotype. It has recently been suggested that cancer cells exhibiting these same abnormal functional characteristics also exhibit dramatic changes in their metabolism and it is these metabolic changes that are the principal cause of all the abnormal cell characteristics. In this proposal, we will test the hypothesis that metabolic abnormalities similar to those observed in cancer cells exist in cells of the pulmonary vasculature and that they control the proliferative and inflammatory behavior of cells. Importantly, we also propose that these metabolic abnormalities can be targeted with specific pharmacologic therapies to reverse the cell abnormalities and mitigate pulmonary hypertension. We propose a series of experiments, which will allow us to determine precisely how the metabolic abnormalities arise, how they direct the abnormalities of cell phenotype that contribute directly to PH, and lastly how we can interrupt this process to achieve better outcomes. We believe these studies will lay the groundwork for a new treatment strategy that targets multiple molecular abnormalities in PH simultaneously and thus, we speculate, will be potentially more effective and achieve greater benefits than the current therapeutic approaches. We also believe these studies will open the door to potential new diagnostics to assess the disease progression as well as responses to therapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510280
Entities
People
- Kurt R Stenmark
Organizations
- United States Army
- University of Colorado Denver