Pulmonary hypertension develops in patients with alveolar hypoxia arising from chronic lung diseases or high altitude exposure. These diseases affect large numbers of patients, and hypoxia-induced pulmonary vascular remodeling is the most common cause of pulmonary hypertension (PH). We propose that remodeling is triggered by mitochondrial O2 sensors that initiate redox signaling in vascular smooth muscle, thereby promoting cell contraction, growth and proliferation. Our previous work implicates mitochondria as a source of reactive oxygen species (ROS) signals that activate functional responses to acute hypoxia in pulmonary artery smooth muscle cells (PASMC). We now propose to test whether these signals also drive vascular remodeling and metabolic reprogramming in PASMC, leading to PH during chronic hypoxia. The role of ROS in PH has been highly controversial, so these studies are critically important for clarifying this issue. Chronic hypoxia activates redox signaling and induces Hypoxia-Inducible Factors (HIF-1 and HIF-2) in pulmonary vascular cells. This promotes metabolic reprogramming toward glycolysis and away from mitochondrial oxidative phosphorylation. We will test whether this reprogramming promotes vascular remodeling and PH. Hypoxia and ROS also activate AMP- dependent Protein Kinase (AMPK), a cellular energy sensor that activates catabolic pathways and inhibits anabolic metabolism, potentially opposing the remodeling response. We will determine whether AMPK activation can limit the growth, proliferation and metabolic reprogramming of PASMC, thereby opposing the development of PH. To achieve these aims we have assembled a powerful set of tools to quantify and modify redox signaling and metabolic pathways, which will be applied in genetic mouse models of PH and in pulmonary vascular cells from patients with pulmonary hypertension. These studies will provide novel insight into the mechanisms regulating the remodeling and PH arising in response to chronic hypoxia, and will identify potential therapeutic targets for the treatment of hypoxia-associated PH in humans.
This project will identify the cellular mechanisms that regulate pulmonary vascular remodeling and the development of pulmonary hypertension in response to hypoxic lung disease or high altitude residence. Specific areas of research will include determining the role of reactive oxygen species signals from mitochondria in triggering the remodeling response, and determine whether blocking this signaling can prevent it;determining whether mitochondrial oxidant signals also trigger metabolic reprogramming in pulmonary vascular cells, causing a shift toward glycolysis and away from mitochondrial respiration that drives growth and proliferation;and determining whether mitochondrial oxidant signals trigger AMP-regulated protein kinase (AMPK), and whether amplification of this response can halt the metabolic reprogramming, growth and proliferation of pulmonary vascular cells, thereby halting the development of pulmonary hypertension.
|Arulkumaran, Nishkantha; Deutschman, Clifford S; Pinsky, Michael R et al. (2016) MITOCHONDRIAL FUNCTION IN SEPSIS. Shock 45:271-81|
|Surmeier, D James; Schumacker, Paul T; Guzman, Jaime D et al. (2016) Calcium and Parkinson's disease. Biochem Biophys Res Commun :|
|Israeli, Eitan; Dryanovski, Dilyan I; Schumacker, Paul T et al. (2016) Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy. Hum Mol Genet 25:2143-2157|
|MartÃnez-Reyes, Inmaculada; Diebold, Lauren P; Kong, Hyewon et al. (2016) TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Mol Cell 61:199-209|
|Waypa, Gregory B; Smith, Kimberly A; Schumacker, Paul T (2016) O2 sensing, mitochondria and ROS signaling: The fog is lifting. Mol Aspects Med 47-48:76-89|
|Chandel, Navdeep S; Avizonis, Dania; Reczek, Colleen R et al. (2016) Are Metformin Doses Used in Murine Cancer Models Clinically Relevant? Cell Metab 23:569-70|
|Ayanga, Bernard A; Badal, Shawn S; Wang, Yin et al. (2016) Dynamin-Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic Nephropathy. J Am Soc Nephrol 27:2733-47|
|Weinberg, Samuel E; Sena, Laura A; Chandel, Navdeep S (2015) Mitochondria in the regulation of innate and adaptive immunity. Immunity 42:406-17|
|Datta, Ankur; Kim, Gina A; Taylor, Joann M et al. (2015) Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent. Am J Physiol Lung Cell Mol Physiol 309:L369-77|
|Reczek, Colleen R; Chandel, Navdeep S (2015) ROS-dependent signal transduction. Curr Opin Cell Biol 33:8-13|
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