Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension

Am J Physiol Lung Cell Mol Physiol. 2019 May 1;316(5):L723-L737. doi: 10.1152/ajplung.00058.2018. Epub 2019 Jan 17.


Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O2 consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.

Keywords: exosome; glutamate dehydrogenase; glycolysis; hypertension; hypoxia; pulmonary; pyruvate dehydrogenase; sirtuin 4; tricarboxylic acid cycle.

MeSH terms

  • Animals
  • Cells, Cultured
  • Citric Acid Cycle
  • Disease Models, Animal
  • Exosomes / metabolism*
  • Exosomes / transplantation*
  • Glutamate Dehydrogenase / metabolism
  • Humans
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Muscle / metabolism
  • Models, Biological
  • Myocytes, Smooth Muscle / metabolism
  • Pulmonary Arterial Hypertension / metabolism*
  • Pulmonary Arterial Hypertension / therapy*
  • Pulmonary Artery / metabolism
  • Pyruvate Dehydrogenase Complex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sirtuins / metabolism


  • Pyruvate Dehydrogenase Complex
  • Glutamate Dehydrogenase
  • Sirtuins