Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice

Department of Pharmacology, Tulane University, 1430 Tulane Ave, New Orleans LA 70112, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 06/2008; 28(8):1432-8. DOI: 10.1161/ATVBAHA.108.167205
Source: PubMed


Type 2 diabetes is associated with increased advanced glycation end product (AGE) formation and vasculopathy. We hypothesized that AGEs contribute to resistance artery dysfunction.
Type 2 diabetic db(-)/db(-) (diabetic) and nondiabetic db(-)/db(+) (control) mice were treated with the AGE inhibitor (aminoguanidine: 50 mg/Kg/d) for 3 months. Isolated mesenteric resistance arteries (MRAs) were mounted in an arteriograph. Pressure-induced myogenic tone (MT) was increased in diabetic mice but was unaffected by aminoguanidine treatment. Phenylephrine-induced contraction and nitric oxide donor-induced endothelium-independent relaxation were similar in all groups. In diabetic mice, endothelium-dependent relaxation in response to shear-stress or acetylcholine was altered and was associated with reduced eNOS protein and mRNA expression. Aminoguanidine treatment improved endothelial function and restored eNOS expression. AGE formation and hypoxia markers (plasminogen activator inhibitor 1 and Bnip3) were increased in MRA from diabetic mice and normalized with Aminoguanidine. Primary cultured endothelial cells (ECs) isolated from resistance arteries subjected to high glucose for 48 hours showed decreased eNOS expression and phosphorylation in response to calcium ionophore. High glucose decreased antioxidant protein (MnSOD) and increased prooxidant proteins (gp91phox) expression leading to increased oxidative stress generation, as assessed by DHE staining and endothelial NADH/NADPH oxidase activity. The preincubation of ECs with aminoguanidine restored eNOS-phosphorylation and expression as well as the balance between pro- and antioxidant factors induced by high glucose.
We provide evidence of a link between AGEs, oxidative stress, and resistance artery EC dysfunction in type 2 diabetic mice. Thus, AGEs and oxidative stress may be a potential target for overcoming diabetic microvessels complications.

Download full-text


Available from: Romer Gonzalez-Villalobos
  • Source
    • "It is importat to note that Nox4 have been recently identified as a mitochondrial cytochrome c oxidase subunit IV as being an additional source of ROS in diabetes [55]. An elevation in Nox activity in hyperglycemia can be mediated by AGEs through their specific receptors (RAGEs) that increase Nox subunit gp91 expression [51] [56] [57]. Hyperglycemia can increase an expression of Nox, as it has been shown in endothelium and vascular SMCs [18] [37] [43] [47] [50] [54]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes mellitus (DM) is a complex syndrome which leads to multiple dysfunctions including vascular disorders. Hyperglycemia is considered to be a key factor responsible for the development of diabetic vascular complications and can mediate their adverse effects through multiple pathways. One of those mechanisms is the activation of protein kinase C (PKC). This important regulatory enzyme is involved in a signal transduction of several vascular functions including vascular smooth muscle contractility. Many studies have shown that hyperglycemia in DM results in oxidative stress. Overproduction of reactive oxygen species (ROS) by different oxidases and the mitochondrial electron transport chain (ETC), advanced glycation end products, polyol pathway flux, and hyperglicemia-induced rising in diacylglycerol (DAG) contribute to the activation of PKC. Activation of endothelial PKC in DM leads to endothelium-dependent vasodilator dysfunction. The main manifestations of this are inhibition of vasodilatation mediated by nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostacyclin, and activation of vasoconstriction mediated by endothelin-1 (ET-1), prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). Activated PKC in DM also increases vascular endothelial growth factor (VEGF) expression and activates NADPH oxidases leading to raised ROS production. On the other hand, PKC in DM is involved in enhancement of vascular contractility in an endothelium-independent manner by inactivation of K(+) channels and Ca(2+) sensitization of myofilaments in vascular smooth muscle cells. This shows that PKC is a potential therapeutic target for treating vascular diabetic complications.
    Full-text · Article · Apr 2014 · International journal of cardiology
  • Source
    • "The main limitation of these previous works is that diabetic rats were very young and thus submitted to a very short period of diabetes (a few weeks). AGEs are generated by non-enzymatic glycation of structural proteins by glucose, a process accompanying normal aging and occurring at an accelerated rate in diabetes [11,12]. As the frequency of type 2 diabetes increases with age and vascular damages associated with diabetes develop over time [3] we investigated flow-mediated remodeling in older ZDF rats and assessed the ability of ALT-711, alone or in combination with an antioxidant, to improve outward remodeling and endothelium-mediated dilation in type 2 diabetic rats. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A chronic increase in blood flow in resistance arteries is associated with increased lumen diameter (outward remodeling) and improved endothelium (NO)-mediated relaxation. Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases. Nevertheless, it is impaired in 12 to 24-month old rats and in young Zucker Diabetic Fatty (ZDF) rats due to advanced glycation end products (AGEs) and oxidative stress. As type 2 diabetes occurs preferentially in older subjects we investigated flow-mediated remodeling and the effect of the AGEs breaker ALT-711 associated or not to the antioxidant TEMPOL in one-year old lean (LZ) and ZDF rats. Mesenteric resistance arteries were exposed to high (HF) or normal blood flow (NF) in vivo. They were collected after 2 weeks for in vitro analysis. In LZ rats, diameter expansion did not occur despite a significant increase in blood flow in HF arteries. Nevertheless, endothelium-mediated relaxation was higher in HF than in NF arteries. ALT-711, alone or in combination with TEMPOL, restored outward remodeling in HF arteries in association with AGEs reduction. TEMPOL alone had no effect. ALT-711, TEMPOL or the combination of the 2 drugs did not significantly affect endothelium-mediated relaxation in HF and NF arteries.In ZDF rats, diameter did not increase despite the increase in blood flow and endothelium-mediated relaxation was further decreased in HF arteries in association with AGEs accumulation and excessive oxidative stress. In both NF and HF arteries, endothelium-mediated relaxation was lower in ZDF than in LZ rats. ALT-711, TEMPOL or their combination did not improve remodeling (diameter equivalent in HF and NF arteries). In parallel, they did not reduce AGEs level and did not improve MMPs activity. Nevertheless, ALT-711 and TEMPOL partly improved endothelium-mediated relaxation through a reduction of oxidative stress and the association of ALT-711 and TEMPOL fully restored relaxation to the level found in LZ rats. ALT-711 did not improve outward remodeling in mature ZDF rats but it reduced oxidative stress and consequently improved endothelium-dependent relaxation. In mature LZ rats, ALT-711 improved outward remodeling and reduced AGEs level. Consequently, AGEs breaking is differently useful in ageing whether it is associated with diabetes or not.
    Full-text · Article · Mar 2014 · Cardiovascular Diabetology
  • Source
    • "In our study, diabetes, ET, GSE and combined ET and GSE did not change the coronary vascular bed response to PE, which is in agreement with others (17, 53), although a reduction (10, 54) and increment (55) in this response have also been reported. Some factors that describe these discrepancies are attributed to the duration of diabetes and to the animal species and vascular bed studied (54). "
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the known complications of diabetes mellitus is vascular dysfunction. Inability of the coronary vascular response to cardiac hyperactivity might cause a higher incidence of ischemic heart disease in diabetic subjects. It has been indicated that regular exercise training and antioxidants could prevent diabetic cardiovascular problems enhanced by vascular damage. The aim of this study was to determine the effects of grape seed extract (as antioxidant), with and without exercise training on coronary vascular function in streptozotocin induced diabetic rats. Fifty male Wistar rats weighing 200 - 232 grams were randomly divided into five groups of 10 rats each: sedentary control, sedentary diabetic, trained diabetic, grape seed extract (200 mg/kg) treated sedentary diabetic and, grape seed extract treated trained diabetic. Diabetes was induced by one intraperitoneal injection of streptozotocin. After eight weeks, coronary vascular responses to vasoactive agents were determined. The endothelium dependent vasorelaxation to acetylcholine was reduced significantly in diabetic animals; exercise training or grape seed extract administration partially improves this response. However, exercise training in combination with grape seed extract restores endothelial function completely. The endothelium independent vasorelaxation to sodium nitroprusside was improved by combination of exercise training and grape seed extract. On the other hand, the basal perfusion pressure and vasoconstrictive response to phenylephrine did not change significantly. The data indicated that co-administration of grape seed extract and exercise training had more significant effects than exercise training or grape seed extract alone; this may constitute a convenient and inexpensive therapeutic approach to diabetic vascular complications.
    Full-text · Article · Oct 2013
Show more