Bioenergetic impairment in Group 3 pulmonary hypertension

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Pulmonary hypertension (PH) resulting from underlying chronic lung disease (Group 3, CLD-PH) is a common disorder associated with significant symptoms and risk of death. Traditional concepts of CLD-PH pathogenesis focus on mechanisms of hypoxic pulmonary vasoconstriction yet vasodilating therapies have failed to provide benefit for CLD-PH patients. Current evidence indicates that pro-proliferative and anti-apoptotic changes in pulmonary vascular cells lead to CLD-PH through progressive pulmonary vascular remodeling. Altered mitochondrial energy metabolism plays a key role in this pulmonary vascular remodeling and is a potential but unexploited treatment target. This proposal outlines research and training that will enable the PI to build on his experience in clinical PH care and epidemiology. The PI’s long-term goal is to become an independent collaborative leader in patient-oriented clinical and translational research focused on developing and evaluating novel treatment approaches for CLD-PH. To achieve this goal, the PI will require further training in: 1) practical and theoretical aspects of cellular metabolic phenotyping and application to human samples; and 2) conduct of prospective clinical trials to assess mechanistically-targeted interventions in patients with PH. Abundant preclinical evidence demonstrates that reductions in the expression and function of the major metabolic regulator, peroxisome proliferator-activated receptor gamma (PPARγ), play a critical role in mitochondrial and metabolic derangements in pulmonary vascular cells. Evolving evidence demonstrates that abnormal mitochondrial metabolism extends beyond pulmonary vascular tissues and is observed in right ventricle cardiomyocytes, skeletal muscle, and circulating platelets, suggesting more global metabolic perturbations in PH. Further, activation of PPARγ with clinically available, antidiabetic, thiazolidinedione (TZD) medications can prevent or reverse experimental PH. The overarching hypothesis for this project is that mitochondrial bioenergetic derangements in CLD-PH are reflected in circulating platelets and can be improved with TZD therapy. Aim 1 will examine platelet glycolytic and mitochondrial bioenergetic function in a cross-sectional study recruiting subjects with CLD-PH, CLD without PH, and healthy controls. The proposed studies will provide the first definition of bioenergetic function in freshly isolated CLD-PH platelets and test for ex vivo treatment with pioglitazone (a TZD). Aim 2 will involve a phase 2 randomized cross-over trial to assess the metabolic impact of pioglitazone in CLD-PH patients. The influence of pioglitazone versus placebo on mitochondrial energy production will be assessed (primary mechanistic outcome) as well as safety and disease efficacy (secondary outcomes). The proposal leverages an outstanding training plan and environment with the support of an experienced multi-dimensional mentorship team to address a critical clinical need in the field of pulmonary vascular biology. Completion of the proposed training and studies will position the PI to compete successfully for independent funding and exert durable impact on the clinical management of PH.