title: Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats.
abstract: Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-product (AGE)-induced vascular remodeling likely contributes. We tested the hypothesis that AGE-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance and altered in-stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, and arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor-β (TGF-β) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD vs. ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGF-β expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. In conclusion, ALT-711 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE-independent pathways. The study supports an important role for AGE-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM.
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin;
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Judy R
authors.initials: JR
authors.lastname: Kersten
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; Department of Orthopaedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Toth
authors.affiliation: Department of Biomedical Engineering, University of California Davis, Davis, California;
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Passerini
authors.affiliation: Department of Biomedical Engineering, University of California Davis, Davis, California;
authors.forename: Anita
authors.initials: A
authors.lastname: Rajamani
authors.affiliation: Transplant and Stem Cell Immunobiology Laboratory, University Heart Center and Cardiovascular Research Center, University of Hamburg, Hamburg, Germany; Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California;
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; Department of Medicine, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin john.ladisa@marquette.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: LaDisa
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000187:drug effects / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000378:metabolism*; D008297:Male; D058426:Neointima / Q000378:metabolism* / Q000517:prevention & control; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D000067759:Receptor for Advanced Glycation End Products / Q000187:drug effects / Q000378:metabolism; D033081:Shear Strength; D015607:Stents; D013314:Stress, Mechanical; D013844:Thiazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: C000593874:Ager protein, rat; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D013844:Thiazoles; D016212:Transforming Growth Factor beta; D003094:Collagen; C406794:alagebrium
keywords: coronary artery disease; hemodynamics; hyperglycemia; interventional cardiology; restenosis