title: FOXO1 mediates the autocrine effect of endothelin-1 on endothelial cell survival.
abstract: Chronic hyperglycemia exerts a deleterious effect on endothelium, contributing to endothelial dysfunction and microvascular complications in poorly controlled diabetes. To understand the underlying mechanism, we studied the effect of endothelin-1 (ET-1) on endothelial production of Forkhead box O1 (FOXO1), a forkhead transcription factor that plays an important role in cell survival. ET-1 is a 21-amino acid peptide that is secreted primarily from endothelium. Using adenovirus-mediated gene transfer approach, we delivered FOXO1 cDNA into cultured human aorta endothelial cells. FOXO1 was shown to stimulate B cell leukemia/lymphoma 2-associated death promoter (BAD) production and promote cellular apoptosis. This effect was counteracted by ET-1. In response to ET-1, FOXO1 was phosphorylated and translocated from the nucleus to cytoplasm, resulting in inhibition of BAD production and mitigation of FOXO1-mediated apoptosis. Hyperglycemia stimulated FOXO1 O-glycosylation and promoted its nuclear localization in human aorta endothelial cells. This effect accounted for unbridled FOXO1 activity in the nucleus, contributing to augmented BAD production and endothelial apoptosis under hyperglycemic conditions. FOXO1 expression became deregulated in the aorta of both streptozotocin-induced diabetic mice and diabetic db/db mice. This hyperglycemia-elicited FOXO1 deregulation and its ensuing effect on endothelial cell survival was corrected by ET-1. Likewise, FoxO1 deregulation in the aorta of diabetic mice was reversible after the reduction of hyperglycemia by insulin therapy. These data reveal a mechanism by which FOXO1 mediated the autocrine effect of ET-1 on endothelial cell survival. FOXO1 deregulation, resulting from an impaired ability of ET-1 to control FOXO1 activity in endothelium, may contribute to hyperglycemia-induced endothelial lesion in diabetes.
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Cifarelli
authors.forename: Sojin
authors.initials: S
authors.lastname: Lee
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Adama
authors.initials: A
authors.lastname: Kamagate
authors.forename: Sandra
authors.initials: S
authors.lastname: Slusher
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bertera
authors.forename: Patrizia
authors.initials: P
authors.lastname: Luppi
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.forename: H Henry
authors.initials: HH
authors.lastname: Dong
mesh_terms: D000818:Animals; D001011:Aorta; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D010766:Phosphorylation; D011897:Random Allocation; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
chemical_list: C494819:BAD protein, human; D019332:Endothelin-1; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D051025:bcl-Associated Death Protein