The metabolic theory of pulmonary arterial hypertension

Circ Res. 2014 Jun 20;115(1):148-64. doi: 10.1161/CIRCRESAHA.115.301130.


Numerous molecular abnormalities have been described in pulmonary arterial hypertension (PAH), complicating the translation of candidate therapies to patients because, typically, 1 treatment addresses only 1 abnormality. The realization that in addition to pulmonary artery vascular cells, other tissues and cells are involved in the syndrome of PAH (eg, immune cells, right ventricular cardiomyocytes, skeletal muscle) further complicates the identification of optimal therapeutic targets. Here, we describe a metabolic theory that proposes that many apparently unrelated molecular abnormalities in PAH do have a common denominator; they either cause or promote a mitochondrial suppression (inhibition of glucose oxidation) in pulmonary vascular cells; in turn, the signaling downstream from this mitochondrial suppression can also explain numerous molecular events previously not connected. This integration of signals upstream and downstream of mitochondria has similarities to cancer and can explain many features of the PAH vascular phenotype, including proliferation and apoptosis resistance. This suppression of glucose oxidation (with secondary upregulation of glycolysis) also underlies the abnormalities in extrapulmonary tissues, suggesting a global metabolic disturbance. The metabolic theory places mitochondria at the center stage for our understanding of PAH pathogenesis and for the development of novel diagnostic and therapeutic tools. Current PAH therapies are each addressing 1 abnormality (eg, upregulation of endothelin-1) and were not developed specifically for PAH but for systemic vascular diseases. Compared with the available therapies, mitochondria-targeting therapies have the advantage of addressing multiple molecular abnormalities simultaneously (thus being potentially more effective) and achieving higher specificity because they address PAH-specific biology.

Keywords: hypertension, pulmonary; metabolism; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Endoplasmic Reticulum Stress
  • Familial Primary Pulmonary Hypertension
  • Glucose / metabolism
  • Heart Ventricles / metabolism
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Ion Channels / physiology
  • Mitochondria / physiology*
  • Mitochondrial Proteins / physiology
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Signal Transduction
  • Uncoupling Protein 2


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ion Channels
  • Mitochondrial Proteins
  • Uncoupling Protein 2
  • Glucose