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

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...

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Bibliographic Details
Published in:	American journal of physiology. Lung cellular and molecular physiology Vol. 316; no. 5; p. L723
Main Authors:	Hogan, Sarah E, Rodriguez Salazar, Maria Pia, Cheadle, John, Glenn, Rachel, Medrano, Carolina, Petersen, Thomas H, Ilagan, Roger M
Format:	Journal Article
Language:	English
Published:	United States 01-05-2019
Subjects:	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 hypoxia tricarboxylic acid cycle glutamate dehydrogenase sirtuin 4 glycolysis pulmonary exosome hypertension
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Summary:	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 O 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.
ISSN:	1522-1504
DOI:	10.1152/ajplung.00058.2018