title: Reducing Vascular Calcification by Anti-IL-1β Monoclonal Antibody in a Mouse Model of Familial Hypercholesterolemia.
abstract: BACKGROUND
  Given the link between cholesterol and activation of inflammation via interleukin 1β (IL-1β), we tested the effects of IL-1β inhibition on atherosclerotic calcification in mice. Patients with familial hypercholesterolemia develop extensive aortic calcification and calcific aortic stenosis. Although statins delay this process, low-density lipoprotein (LDL) cholesterol lowering alone is not enough to avert it. Data suggest that vascular inflammation initiated by hypercholesterolemia is followed by unchecked mineralization at sites of atherosclerotic plaques. The LDL-receptor (LDLR)-deficient (Ldlr(-/-)) and LDLR-attenuated Pcsk9(Tg) mice are available animal models for pharmacological testing.
  
  
  METHODS
  A mouse monoclonal antibody (mAb) against IL-1β or placebo was administered subcutaneously in Ldlr(-/-) and Pcsk9(Tg) models fed a Western diet. Drug level, anthropometric, lipid, and glucose profiles were determined. Expressions of proprotein convertase subtilisin/kexin type 9 (PCSK9), serum amyloid A1, and cytokine were measured by enzyme-linked immunosorbent assay. Aortic calcification was determined by microcomputerized tomography (micro-CT) and X-ray densitometry, and aortic flow velocity was assessed by ultrasound.
  
  
  RESULTS
  Circulating levels of IL-1β in Ldlr(-/-) mice were significantly greater (2-fold) than observed in Pcsk9(Tg) mice. Placebo- and mAb-treated mice did not differ in their growth, lipid, glucose profiles, and other cytokines. Calcifications were significantly diminished in mAb-treatment Ldlr(-/-) mice (a reduction of ∼ 75% by X-ray and ∼ 90% by micro-CT) and reduced insignificantly in mAb-treatment Pcsk9(Tg) mice, whereas aortic flow velocity was unchanged in both models.
  
  
  CONCLUSIONS
  Herein, we demonstrate that aortic calcifications can be inhibited by an IL-1β mAb in LDLR-deficient mice. These results have a translational component to prevent vascular calcification in human and represent new evidence to rationalize targeting inflammation in cardiovascular disease.
authors.affiliation: Division of Clinical Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia zawan@kau.edu.sa.
authors.forename: Zuhier
authors.initials: Z
authors.lastname: Awan
authors.affiliation: The Department Cardiology, McGill University, Montréal, Québec, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Denis
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Roubtsova
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: Rachid
authors.initials: R
authors.lastname: Essalmani
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Marcinkiewicz
authors.affiliation: Division of Clinical Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Amani
authors.initials: A
authors.lastname: Awan
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.affiliation: Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: The Department Cardiology, McGill University, Montréal, Québec, Canada jacques.genest@muhc.mcgill.ca.
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001011:Aorta / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001018:Aortic Diseases / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D001027:Aortography / Q000379:methods; D015415:Biomarkers / Q000097:blood; D001783:Blood Flow Velocity; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012039:Regional Blood Flow; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014463:Ultrasonography; D061205:Vascular Calcification / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D055114:X-Ray Microtomography
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D015415:Biomarkers; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D011973:Receptors, LDL; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: IL-1β; LDLR; PCSK9; aortic calcification; familial hypercholesterolemia