Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats
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Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats. / Wang, Hongfeng; Weihrauch, Dorothee; Kersten, Judy R; Toth, Jeffrey M; Passerini, Anthony G; Rajamani, Anita; Schrepfer, Sonja; LaDisa, John F.
in: AM J PHYSIOL-HEART C, Jahrgang 309, Nr. 7, 10.2015, S. 1130-1140.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats
AU - Wang, Hongfeng
AU - Weihrauch, Dorothee
AU - Kersten, Judy R
AU - Toth, Jeffrey M
AU - Passerini, Anthony G
AU - Rajamani, Anita
AU - Schrepfer, Sonja
AU - LaDisa, John F
N1 - Copyright © 2015 the American Physiological Society.
PY - 2015/10
Y1 - 2015/10
N2 - 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.
AB - 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.
KW - Animals
KW - Aorta, Abdominal/drug effects
KW - Collagen/drug effects
KW - Diabetes Mellitus/metabolism
KW - Glycation End Products, Advanced/drug effects
KW - Graft Occlusion, Vascular/metabolism
KW - Male
KW - Neointima/metabolism
KW - Obesity/metabolism
KW - Rats
KW - Rats, Zucker
KW - Receptor for Advanced Glycation End Products/drug effects
KW - Shear Strength
KW - Stents
KW - Stress, Mechanical
KW - Thiazoles/pharmacology
KW - Transforming Growth Factor beta/drug effects
KW - Vascular Resistance/drug effects
U2 - 10.1152/ajpheart.00123.2014
DO - 10.1152/ajpheart.00123.2014
M3 - SCORING: Journal article
C2 - 26254329
VL - 309
SP - 1130
EP - 1140
JO - AM J PHYSIOL-HEART C
JF - AM J PHYSIOL-HEART C
SN - 0363-6135
IS - 7
ER -