Kurt Stenmark, MD

Website: https://scholar.google.com/citations?user=-KmBZywAAAAJ&hl=en&oi=ao

For Patients:
My laboratory is interested in determining the cellular and molecular mechanisms that contribute to structural remodeling of the pulmonary vasculature and to right heart dysfunction in the setting of pulmonary hypertension (PH). Pulmonary vascular remodeling is observed in all forms of chronic pulmonary hypertension and is thought to contribute significantly to the increase in pulmonary vascular resistance and ultimately to the right heart failure that determines the outcomes of patients with pulmonary hypertension. An emerging “metabolic theory” of PH suggests that metabolic and mitochondria-based remodeling may underlie the pathology of these tissues, explain many clinical features of PAH, and provide novel biomarkers and therapeutic targets for future interventions. Metabolic reprogramming has been increasingly recognized as a key driver of cancer. In addition to uncontrolled proliferation, hallmarks of cancer also include induction of angiogenesis and chronic inflammation, two features also shared with PH. Moreover, as observed in cancer cells, PH cells are well documented to rewire their metabolism and energy production network (elevated glucose uptake, increased lactate production, and accumulation of glycolytic intermediates regardless of oxygen availability) to support the high proliferation: a phenomenon known as Warburg effect. These results are consistent with the studies in IPAH patients, showing that some IPAH patients exhibit upregulated glycolytic gene expression and increased glucose uptake. Our recent work supports the idea that at least in fibroblasts from the hypertensive vessels, the Warburg effect is in fact a well-orchestrated adaptation/reprogramming of mitochondrial function that can be directly linked to epigenetic changes in gene expression. Our research has also revealed that the dichotomy between glycolysis and oxidative phosphorylation in PH-cells might not be as rigid as previously thought. Decreased pyruvate export to the mitochondria and accumulation of metabolites of glycolysis consistent with the necessity to recycle oxidized glutathione (increased levels of oxidized glutathione, impaired GSH/GSSG ratios, and elevated ROS levels). Furthermore, PH-fibroblasts mostly used glutamine to generate glutamate, both to synthesize reduced glutathione (to partially counteract oxidative stress) and fuel the Krebs cycle through the generation of alpha-ketoglutarate. However, increased oxidative stress affected oxygen consumption rates at the Complex I level, resulting in a metabolic blockade in late Krebs cycle reactions. These findings revealed that the glycolysis and mitochondrial metabolism cooperation is more dynamic than previously thought. This unique metabolic phenotype, which PH-cells exhibit and the normal cells lack, could be a potential biochemical feature for targeted drug selection. Deciphering of the mechanisms that underline this distinct metabolic reprogramming and identification of a novel, selective, and promising molecular target to alleviate and ultimately cure PH is one of the over-arching goals of our laboratory.

For Referring Providers:
My research focuses on understanding the cellular and metabolic mechanisms driving pulmonary vascular remodeling and right heart dysfunction in pulmonary hypertension (PH). By exploring unique metabolic features in PH, we aim to identify biomarkers and targeted therapies to improve patient outcomes. My goal is to translate these findings into innovative approaches for managing and treating PH.