Caveolin-1 is a critical determinant of autophagy, metabolic switching, and oxidative stress in vascular endothelium.
Caveolin-1 is a scaffolding/regulatory protein that interacts with diverse signaling molecules. Caveolin-1(null) 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-1(null) 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.
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Takashi
T
Shiroto
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Natalia
N
Romero
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Toru
T
Sugiyama
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Juliano L
JL
Sartoretto
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Hermann
H
Kalwa
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Zhonghua
Z
Yan
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Hiroaki
H
Shimokawa
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Thomas
T
Michel
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D001343:Autophagy; D002374:Catalase / Q000378:metabolism; D002417:Cattle; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione