The Basic Science of Metabolism in Pulmonary Arterial Hypertension

Abstract

Pulmonary hypertension (PH) encompasses a group of progressive and incurable cardiopulmonary disorders characterized by pulmonary vascular remodeling and increased mean pulmonary artery pressure leading to right heart failure. Emerging data suggest a common etiology for the reported diverse molecular and physiological abnormalities observed in the pulmonary vasculature: the metabolic theory of PH. This theory proposes that aberrations in metabolism and mitochondrial function are a major underlying cause for the cellular and organ level PH phenotype. Additionally, the metabolic theory of PH provides a rationale for the observed metabolic defects in other organs and systems outside of the pulmonary vasculature, including the right ventricle (RV), immune system, and skeletal muscle. However, whether these metabolic changes are driving disease and the timing and extent of these aberrations are still unknown. This review highlights: 1) key examples of metabolic alterations in the pulmonary vasculature, RV, inflammatory cells, and skeletal muscle; 2) examples of promising therapeutic interventions directly modifying metabolism; and 3) key remaining questions about the role of metabolic remodeling in PH.

Effects of macitentan and tadalafil monotherapy or their combination on the right ventricle and plasma metabolites in pulmonary hypertensive rats

“…Initially, we searched for metabolites, which were significantly altered by disease versus healthy control and we investigated if the agents used were able to recover those changes in both SuHx and PAB rats. Evidence suggests that changed metabolism plays a key role in PAH pathogenesis 36 and a number of novel pharmacological agents targeting those changes are under investigation for their effects in PAH. 37 In addition, several circulating metabolites determine the adverse outcome of patients with PAH 38 serving as potential biomarkers.…”

Endurance exercise training in pulmonary hypertension increases skeletal muscle electron transport chain supercomplex assembly

“…Exercise intolerance in PAH has been attributed to both an underlying global metabolic disorder affecting the muscles as well as microcirculatory perfusion alterations potentially related to central hemodynamic impairments. 2,47,48 Decreased capillary density or rarefaction has been documented in the SkM of animal models of PAH as well as patients. 2,48,49 In addition, the VEGFR inhibitor SU5416 required to initiate PAH may reduce angiogenic responses.…”

Glutaminolysis: A Driver of Vascular and Cardiac Remodeling in Pulmonary Arterial Hypertension

“…Whereas energy generation is less useful for glycolysis per glucose molecule, some earlier studies posited that enough glucose is available in the pulmonary vessels sufficient for ATP production to drive cellular proliferation ( 31 ). Nonetheless, a decrease of carbon intermediates, independent of ATP production, conjointly occurs if glucose is jolted away from the tricarboxylic acid (TCA) cycle, hence negatively impacting the carbon substrates employed in the production of nucleotides and proteins ( 41 ). Anaplerosis (the process by which carbon intermediates of the TCA cycle are replenished) is crucial in preserving cell mass (nucleotides and proteins), mainly if glycolysis is predominant.…”