title: Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease.
abstract: Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsui
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Yukiji
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Uemura
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Seno
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Onoue
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsushima
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Tsunenari
authors.initials: T
authors.lastname: Soeda
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okayama
authors.affiliation: 1] First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan [2] Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Somekawa
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Samejima
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawata
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kawakami
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Nakatani
authors.affiliation: First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Iwano
authors.affiliation: 1] First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan [2] Department of Regulatory Medicine for Blood Pressure, Kashihara, Nara, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006493:Heparin / Q000008:administration & dosage; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018384:Oxidative Stress; D000072483:Placenta Growth Factor; D011237:Predictive Value of Tests; D011257:Pregnancy Proteins / Q000097:blood; D011379:Prognosis; D020033:Protein Isoforms; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D012307:Risk Factors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood* / Q000172:deficiency / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D000072483:Placenta Growth Factor; D006493:Heparin; C501162:FLT1 protein, human; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1