title: The AGE-breaker ALT-711 restores high blood flow-dependent remodeling in mesenteric resistance arteries in a rat model of type 2 diabetes.
abstract: Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases, but this is impaired in diabetes. We hypothesized that breaking advanced glycation end product (AGE) cross-links could improve remodeling in mesenteric resistance arteries in Zucker diabetic fatty (ZDF) rats compared with lean Zucker (LZ) rats. Arteries, exposed to high (HF) or normal (NF) blood flow after alternate arterial ligation in vivo, were collected after 2 weeks. In LZ rats, HF artery diameter was larger than for NF vessels, but this was not the case in ZDF rats. Endothelium-mediated dilation in ZDF rats, which was lower than in LZ rats, was further decreased in HF arteries. Treatment of rats with the AGE-breaker 4,5-dimethyl-3-phenacylthiazolium chloride (ALT-711) (3 mg/kg/day; 3 weeks) reversed diabetes-induced impairment of HF-dependent remodeling. ALT-711 also improved endothelium nitric oxide-dependent relaxation in mesenteric resistance arteries. Reactive oxygen species reduction restored relaxation in ZDF rats but not in LZ or ALT-711-treated rats. AGEs were reduced in ALT-711-treated ZDF rats compared with ZDF rats. Metalloproteinase activity, necessary for HF-dependent remodeling, was reduced in ZDF rats compared with LZ rats and restored by ALT-711. Thus, targeting AGE cross-links may provide a therapeutic potential for overcoming microvascular complications in ischemic disorders occurring in diabetes.
authors.affiliation: Department of Integrated Neurovascular Biology, INSERM U771,MCentre National de la Recherche Scientifique UMR 6214, UniversitéMd’Angers, Angers, France.
authors.forename: Mohamed L
authors.initials: ML
authors.lastname: Freidja
authors.forename: Kahena
authors.initials: K
authors.lastname: Tarhouni
authors.forename: Bertrand
authors.initials: B
authors.lastname: Toutain
authors.forename: Céline
authors.initials: C
authors.lastname: Fassot
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D017127:Glycation End Products, Advanced; D013844:Thiazoles; C406794:alagebrium