Role of Mitochondrial/Metabolic Reprogramming in Controlling Aberrant Gene Expression 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 frequently associated with chronic lung disorders, such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, obesity, and viral infections, which are all extremely 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 pulmonary arterial hypertension (PAH), none of the drugs shown to be useful for these patients have shown any benefit in patients with chronic hypoxic lung diseases, such as COPD, or lung fibrosis, and in fact some patients given these drugs have had adverse side effects. 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 minimally reversible with supplemental oxygen. This may be due to the structural changes in the lung blood vessels of these patients. These vessels exhibit thickening and fibrotic changes due to excessive proliferation and resistance to normal death of resident pulmonary vascular wall cells. Recent studies 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, smooth muscle cells and fibroblasts), have recently been shown to exhibit many of the same features as cancer cells including excessive proliferation, resistance to death, and a hyperinflammatory phenotype. While cancer is driven by genetic mutation in genes, it has recently been shown by our group and others that the changes in cell function in cells in chronic lung vascular disease are not due to genetic changes but rather to acquired changes in gene expression, referred to as epigenetic changes. These epigenetic changes are often the result of changes in the metabolic state of the cell. In this proposal, which is driven by exciting new data produced in our now expiring Department of Defense grant, we test the idea that the persistence of functional abnormalities in cells from patients with chronic lung vascular disease, can be effectively and safely normalized by treatment with drugs aimed at restoring metabolism by specifically targeting pathways that control mitochondrial metabolism. Our proposal will directly test whether this idea is correct. 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. Importantly, we propose to examine the idea that exercise, which until recently has been avoided in patients with PH, can benefit patients with PH by directly restoring mitochondrial metabolism back to normal. Understanding how exercise might induce these effects might open the door to using medicine, also targeting metabolism, together with exercise to improve the quality of life in patients with PH. 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 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 simultaneo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010249
Entities
People
- Kurt R Stenmark
Organizations
- United States Army
- University of Colorado Denver