Targeting energetic metabolism: a new frontier in the pathogenesis and treatment of pulmonary hypertension

Abstract

This perspective highlights advances in the understanding of the role of cellular metabolism in the pathogenesis of pulmonary hypertension. Insights gained in the past 20 years have revealed several similarities between the cellular processes underlying the pulmonary vascular remodeling in pulmonary hypertension and those seen in cancer processes. In line with these insights, there is increasing recognition that abnormal cellular metabolism, notably of aerobic glycolysis (the "Warburg effect"), the potential involvement of hypoxia-inducible factor in this process, and alterations in mitochondrial function, are key elements in the pathogenesis of this disease. The glycolytic shift may underlie the resistance to apoptosis and increased vascular cell proliferation, which are hallmarks of pulmonary hypertension. These investigations have led to novel approaches in the diagnosis and therapy of pulmonary hypertension.

Figure 1.

Hypoxia-inducible factor (HIF) activation in pulmonary hypertension (PH). In certain conditions, such as hypoxia, reduced nitric oxide (NO) and manganese superoxide dismutase (MnSOD2), or inhibited prolyl hydroxylases, HIF-1α becomes stabilized and forms a heterodimer with HIF-1β to activate the transcription of over 100 genes, some of which are shown above. Up-regulation of glycolytic enzymes such as glucose transporters (GLUT), hexokinases (HK), phosphofructokinase (PFK), pyruvate kinases (PK), and pyruvate dehydrogenase kinase (PDK) results in a metabolic shift toward glycolysis and away from fatty acid β-oxidation. The up-regulation of certain growth factors including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor (TGF)-β leads to hyperplastic and hypertrophic effects in the pulmonary vasculature. Increased expression of vascular endothelial growth factor (VEGF) contributes to misguided angiogenesis. The up-regulation of stromal-derived growth factor (SDF)-1 with its receptors (CXCR4 and CXCR7) aids in the recruitment of bone marrow precursors which likely contribute to the signaling driving vascular remodeling.

Figure 2.

Increased ¹⁸F-labeled deoxyglucose (FDG) uptake in pulmonary hypertension (PH). (A) Representative positron emission tomography (PET) and computed tomography (CT) images from a patient with idiopathic pulmonary arterial hypertension (IPAH) (bottom) and a healthy control subject (top). PET images are shown on the right, and CT images are shown on the left. (B) Standardized uptake values (SUV) of ¹⁸F-labeled deoxyglucose (FDG)-PET scans in the lungs of patients with IPAH (n = 4) and healthy control subjects (n = 3) at 1.5 and 3 hours after injection (^*,†P = 0.01). Reprinted by permission from Reference .