Pigment epithelium-derived factor inhibits leptin-induced angiogenesis by suppressing vascular endothelial growth factor gene expression through anti-oxidative properties.
Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor, and its vitreous levels are associated with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the molecular mechanism for leptin-elicited angiogenesis remains to be elucidated. Pigment epithelium-derived factor (PEDF) has been shown to be the most potent natural inhibitor of angiogenesis in the mammalian eye, and its levels in the vitreous were decreased in angiogenic eye diseases. In this study, we investigated whether and how PEDF could inhibit the leptin-induced DNA synthesis in microvascular endothelial cells (EC), a key step of angiogenesis. Leptin significantly increased intracellular reactive oxygen species (ROS) generation in microvascular EC. PEDF was found to inhibit the leptin-induced ROS generation in EC. An anti-oxidant, N-acetylcysteine, or PEDF completely prevented the leptin-induced upregulation of vascular endothelial growth factor (VEGF) mRNA levels as well as any increase in DNA synthesis in microvascular EC. Polyclonal antibodies against human VEGF were also found to completely inhibit DNA synthesis in leptin-exposed EC. The present study suggests that leptin could elicit angiogenesis through autocrine VEGF production via intracellular ROS generation. PEDF may block the angiogenic effects of leptin through its anti-oxidative properties.
Yamagishi
Sho-ichi
S
Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Japan. shoichi@med.kurume-u.ac.jp
Amano
Shinjiro
S
Inagaki
Yosuke
Y
Okamoto
Tamami
T
Takeuchi
Masayoshi
M
Inoue
Hiroyoshi
H
D000111:Acetylcysteine / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002417:Cattle; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005128:Eye Diseases / Q000378:metabolism; D005136:Eye Proteins; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020738:Leptin / Q000737:chemistry* / Q000378:metabolism; D008833:Microcirculation / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009414:Nerve Growth Factors; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D054411:Receptors, Leptin; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015861:Retinal Neovascularization; D012171:Retinal Vessels / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000737:chemistry / Q000378:metabolism; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
D000111:Acetylcysteine; D000975:Antioxidants; D004247:DNA; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009414:Nerve Growth Factors; D011506:Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D054411:Receptors, Leptin; D040262:Receptors, Vascular Endothelial Growth Factor; D015843:Serpins; D013936:Thymidine; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C515448:LEPR protein, human