2. Academic Validation
  3. Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats

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. doi: 10.1152/ajpheart.00123.2014.
Hongfeng Wang 1,  Dorothee Weihrauch 2,  Judy R Kersten 2,  Jeffrey M Toth 3,  Anthony G Passerini 4,  Anita Rajamani 4,  Sonja Schrepfer 5,  John F LaDisa Jr 6
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin;
  • 2 Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
  • 3 Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; Department of Orthopaedic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin;
  • 4 Department of Biomedical Engineering, University of California Davis, Davis, California;
  • 5 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;
  • 6 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.
PMID: 26254329 DOI: 10.1152/ajpheart.00123.2014
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.

Keywords

coronary artery disease; hemodynamics; hyperglycemia; interventional cardiology; restenosis.

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