title: Inhibiting C-reactive protein for the treatment of cardiovascular disease: promising evidence from rodent models.
abstract: Raised blood C-reactive protein (CRP) level is a predictor of cardiovascular events, but whether blood CRP is causal in the disease process is unknown. The latter would best be defined by pharmacological inhibition of the protein in the context of a randomized case-control study. However, no CRP specific drug is currently available so such a prospective study cannot be performed. Blood CRP is synthesized primarily in the liver and the liver is an organ where antisense oligonucleotide (ASO) drugs accumulate. Taking advantage of this we evaluated the efficacy of CRP specific ASOs in rodents with experimentally induced cardiovascular damage. Treating rats for 4 weeks with a rat CRP-specific ASO achieved >60% reduction of blood CRP. Notably, this effect was associated with improved heart function and pathology following myocardial infarction (induced by ligation of the left anterior descending artery). Likewise in human CRP transgenic mice treated for 2 weeks with a human CRP-specific ASO, blood human CRP was reduced by >70% and carotid artery patency was improved (2 weeks after surgical ligation). CRP specific ASOs might pave the way towards a placebo-controlled trial that could clarify the role of CRP in cardiovascular disease.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, 1825 University Boulevard, SHEL 214, Birmingham, Al 35294-2182, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, 1825 University Boulevard, SHEL 214, Birmingham, Al 35294-2182, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCrory
authors.affiliation: Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Xing
authors.affiliation: Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Hage
authors.affiliation: Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.affiliation: Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.affiliation: Division of Cardiovascular Disease, The University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Charles River Laboratories, Sparks, NV 89431, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Charles River Laboratories, Sparks, NV 89431, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Early
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Zanardi
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Isis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92008, USA.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy*; D004452:Echocardiography; D005260:Female; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016376:Oligonucleotides, Antisense; D002097:C-Reactive Protein