title: Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E-deficient mice.
abstract: BACKGROUND
  The novel phosphate binder sevelamer has been shown to prevent the progression of aortic and coronary calcification in uremic patients. Whether it also decreases the progression of atheromatous plaques is unknown. The aim of our study was to examine the effect of sevelamer administration on the development of atherosclerosis and aortic calcification in the uremic apolipoprotein E-deficient mouse as an established model of accelerated atherosclerosis.
  
  
  RESULTS
  Female mice were randomly assigned to 4 groups: 2 groups of nonuremic mice (sevelamer versus control) and 2 groups of uremic mice (sevelamer versus control). Sevelamer was given at 3% with chow. The increases in serum phosphorus concentration and calcium-phosphorus product observed in uremic control mice were prevented by sevelamer. Serum total cholesterol was increased in the 2 uremic mouse groups and remained unchanged in response to sevelamer. After 8 weeks of sevelamer treatment, uremic mice exhibited a significantly lower degree of atherosclerosis (P<0.001) and vascular calcification than uremic control mice. Of interest, sevelamer exerted an effect on both intima and media calcification (P=0.005) in uremic mice. Among possible mechanisms involved, we found no evidence for the modulation by sevelamer of inflammation or selected uremic toxins. In contrast, nitrotyrosine staining as a measure of oxidative damage was significantly decreased in response to sevelamer treatment in control and uremic mice (P<0.005).
  
  
  CONCLUSIONS
  Sevelamer delays not only vascular calcification but also atherosclerotic lesion progression in uremic apolipoprotein E-deficient mice. It opens the possibility of a cholesterol-independent action of sevelamer on atheroma formation via effects on mineral metabolism, oxidative stress, or both.
authors.affiliation: INSERM Unit 507, Necker Hospital, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Phan
authors.forename: Ognen
authors.initials: O
authors.lastname: Ivanovski
authors.forename: Thao
authors.initials: T
authors.lastname: Nguyen-Khoa
authors.forename: Nadya
authors.initials: N
authors.lastname: Mothu
authors.forename: Jesus
authors.initials: J
authors.lastname: Angulo
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Natalie
authors.initials: N
authors.lastname: Meert
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.forename: Igor G
authors.initials: IG
authors.lastname: Nikolov
authors.forename: Raymond
authors.initials: R
authors.lastname: Vanholder
authors.forename: Bernard
authors.initials: B
authors.lastname: Lacour
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drüeke
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D010919:Placebos; D011073:Polyamines / Q000627:therapeutic use*; D000069603:Sevelamer; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014511:Uremia / Q000150:complications*
chemical_list: D001057:Apolipoproteins E; D010919:Placebos; D011073:Polyamines; C002744:3-nitrotyrosine; D014443:Tyrosine; D003094:Collagen; D000069603:Sevelamer