Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats. Am J Physiol Heart Circ Physiol 2015 Oct;309(7):H1130-40
Date
08/09/2015Pubmed ID
26254329Pubmed Central ID
PMC4865061DOI
10.1152/ajpheart.00123.2014Scopus ID
2-s2.0-84943144084 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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.
Author List
Wang H, Weihrauch D, Kersten JR, Toth JM, Passerini AG, Rajamani A, Schrepfer S, LaDisa JF JrAuthors
John F. LaDisa PhD Professor in the Pediatrics department at Medical College of WisconsinJeffrey M. Toth PhD Associate Dean for Research in the School of Dentistry department at Marquette University
Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAorta, Abdominal
Collagen
Diabetes Mellitus
Glycation End Products, Advanced
Graft Occlusion, Vascular
Male
Neointima
Obesity
Rats
Rats, Zucker
Receptor for Advanced Glycation End Products
Shear Strength
Stents
Stress, Mechanical
Thiazoles
Transforming Growth Factor beta
Vascular Resistance
