Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence.
Prohibitin 1 (PHB1) is a highly conserved protein that is mainly localized to the inner mitochondrial membrane and has been implicated in regulating mitochondrial function in yeast. Because mitochondria are emerging as an important regulator of vascular homeostasis, we examined PHB1 function in endothelial cells. PHB1 is highly expressed in the vascular system and knockdown of PHB1 in endothelial cells increases mitochondrial production of reactive oxygen species via inhibition of complex I, which results in cellular senescence. As a direct consequence, both Akt and Rac1 are hyperactivated, leading to cytoskeletal rearrangements and decreased endothelial cell motility, e.g., migration and tube formation. This is also reflected in an in vivo angiogenesis assay, where silencing of PHB1 blocks the formation of functional blood vessels. Collectively, our results provide evidence that PHB1 is important for mitochondrial function and prevents reactive oxygen species-induced senescence and thereby maintains the angiogenic capacity of endothelial cells.
Schleicher
Michael
M
Department of Pharmacology, and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06536, USA.
Shepherd
Benjamin R
BR
Suarez
Yajaira
Y
Fernandez-Hernando
Carlos
C
Yu
Jun
J
Pan
Yong
Y
Acevedo
Lisette M
LM
Shadel
Gerald S
GS
Sessa
William C
WC
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D003599:Cytoskeleton / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000091402:Prohibitins; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D042967:Electron Transport Complex I; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D000091402:Prohibitins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; C000717328:PHB protein, human; C484602:Rac1 protein, mouse