Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium

Takashi Shiroto, Natalia Romero, Toru Sugiyama, Juliano L. Sartoretto, Hermann Kalwa, Zhonghua Yan, Hiroaki Shimokawa, Thomas Michel

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Caveolin-1 is a scaffolding/regulatory protein that interacts with diverse signaling molecules. Caveolin-1null mice have marked metabolic abnormalities, yet the underlying molecular mechanisms are incompletely understood. We found the redox stress plasma biomarker plasma 8-isoprostane was elevated in caveolin-1null mice, and discovered that siRNA-mediated caveolin-1 knockdown in endothelial cells promoted significant increases in intracellular H2O2. Mitochondrial ROS production was increased in endothelial cells after caveolin-1 knockdown; 2-deoxy-D-glucose attenuated this increase, implicating caveolin-1 in control of glycolytic pathways. We performed unbiased metabolomic characterizations of endothelial cell lysates following caveolin-1 knockdown, and discovered strikingly increased levels (up to 30-fold) of cellular dipeptides, consistent with autophagy activation. Metabolomic analyses revealed that caveolin-1 knockdown led to a decrease in glycolytic intermediates, accompanied by an increase in fatty acids, suggesting a metabolic switch. Taken together, these results establish that caveolin-1 plays a central role in regulation of oxidative stress, metabolic switching, and autophagy in the endothelium, and may represent a critical target in cardiovascular diseases.

Original languageEnglish
Article numbere87871
JournalPloS one
Volume9
Issue number2
DOIs
Publication statusPublished - 2014 Feb 3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Shiroto, T., Romero, N., Sugiyama, T., Sartoretto, J. L., Kalwa, H., Yan, Z., Shimokawa, H., & Michel, T. (2014). Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium. PloS one, 9(2), [e87871]. https://doi.org/10.1371/journal.pone.0087871