Alagebrium Inhibits Neointimal Hyperplasia and Restores Distributions of Wall Shear Stress by Reducing Downstream Vascular Resistance in Obese and Diabetic Rats

Authors

Hongfeng Wang, Marquette UniversityFollow
Dorothee Weihrauch, Medical College of Wisconsin
Judy R. Kersten, Medical College of Wisconsin
Jeffrey M. Toth, Marquette UniversityFollow
Anthony G. Passerini, University of California - Davis
Anita Rajamani, University of California - Davis
Sonja Schrepfer, University of Hamburg
John F. LaDisa Jr., Marquette UniversityFollow

Document Type

Article

Language

eng

Format of Original

11 p.

Publication Date

10-1-2015

Publisher

American Physiological Society

Source Publication

American Journal of Physiology - Heart and Circulatory Physiology

Source ISSN

0363-6135

Original Item ID

doi: 10.1152/ajpheart.00123.2014

Abstract

Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-products (AGEs)-induced vascular remodeling likely contributes. We tested the hypothesis that AGEs-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance (DVR), 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, arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor beta (TGFβ) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD versus 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 TGFβ 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 AGEs-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM.

Comments

Accepted version. American Journal of Physiology: Heart and Circulatory Physiology, Vol. 309, No. 7 (October 1, 2015): H1130-H1140. DOI. © 2015 American Physiological Society. Used with permission.

Recommended Citation

Wang, Hongfeng; Weihrauch, Dorothee; Kersten, Judy R.; Toth, Jeffrey M.; Passerini, Anthony G.; Rajamani, Anita; Schrepfer, Sonja; and LaDisa, John F. Jr., "Alagebrium Inhibits Neointimal Hyperplasia and Restores Distributions of Wall Shear Stress by Reducing Downstream Vascular Resistance in Obese and Diabetic Rats" (2015). Biomedical Engineering Faculty Research and Publications. 356.
https://epublications.marquette.edu/bioengin_fac/356