Interaction between Advanced Glycation End Products Formation and Vascular Responses in Femoral and Coronary Arteries from Exercised Diabetic Rats

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Abstract

Background

The majority of studies have investigated the effect of exercise training (TR) on vascular responses in diabetic animals (DB), but none evaluated nitric oxide (NO) and advanced glycation end products (AGEs) formation associated with oxidant and antioxidant activities in femoral and coronary arteries from trained diabetic rats. Our hypothesis was that 8-week TR would alter AGEs levels in type 1 diabetic rats ameliorating vascular responsiveness.

Methodology/Principal Findings

Male Wistar rats were divided into control sedentary (C/SD), sedentary diabetic (SD/DB), and trained diabetic (TR/DB). DB was induced by streptozotocin (i.p.: 60 mg/kg). TR was performed for 60 min per day, 5 days/week, during 8 weeks. Concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), phenylephrine (PHE) and tromboxane analog (U46619) were obtained. The protein expressions of eNOS, receptor for AGEs (RAGE), Cu/Zn-SOD and Mn-SOD were analyzed. Tissues NO production and reactive oxygen species (ROS) generation were evaluated. Plasma nitrate/nitrite (NO _x ⁻), superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS) and N ^ε-(carboxymethyl) lysine (CML, AGE biomarker). A rightward shift in the concentration-response curves to ACh was observed in femoral and coronary arteries from SD/DB that was accompanied by an increase in TBARS and CML levels. Decreased in the eNOS expression, tissues NO production and NO _x ⁻ levels were associated with increased ROS generation. A positive interaction between the beneficial effect of TR on the relaxing responses to ACh and the reduction in TBARS and CML levels were observed without changing in antioxidant activities. The eNOS protein expression, tissues NO production and ROS generation were fully re-established in TR/DB, but plasma NO _x ⁻ levels were partially restored.

Conclusion

Shear stress induced by TR fully restores the eNOS/NO pathway in both preparations from non-treated diabetic rats, however, a massive production of AGEs still affecting relaxing responses possibly involving other endothelium-dependent vasodilator agents, mainly in coronary artery.

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Most cited references 59

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Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial.

Ronald Sigal, Glen P Kenny, Normand Boulé … (2007)

Previous trials have evaluated the effects of aerobic training alone and of resistance training alone on glycemic control in type 2 diabetes, as assessed by hemoglobin A1c values. However, none could assess incremental effects of combined aerobic and resistance training compared with either type of exercise alone. To determine the effects of aerobic training alone, resistance training alone, and combined exercise training on hemoglobin A1c values in patients with type 2 diabetes. Randomized, controlled trial. 8 community-based facilities. 251 adults age 39 to 70 years with type 2 diabetes. A negative result on a stress test or clearance by a cardiologist, and adherence to exercise during a 4-week run-in period, were required before randomization. Aerobic training, resistance training, or both types of exercise (combined exercise training). A sedentary control group was included. Exercise training was performed 3 times weekly for 22 weeks (weeks 5 to 26 of the study). The primary outcome was the change in hemoglobin A1c value at 6 months. Secondary outcomes were changes in body composition, plasma lipid values, and blood pressure. The absolute change in the hemoglobin A1c value in the combined exercise training group compared with the control group was -0.51 percentage point (95% CI, -0.87 to -0.14) in the aerobic training group and -0.38 percentage point (CI, -0.72 to -0.22) in the resistance training group. Combined exercise training resulted in an additional change in the hemoglobin A1c value of -0.46 percentage point (CI, -0.83 to -0.09) compared with aerobic training alone and -0.59 percentage point (CI, -0.95 to -0.23) compared with resistance training alone. Changes in blood pressure and lipid values did not statistically significantly differ among groups. Adverse events were more common in the exercise groups. The generalizability of the results to patients who are less adherent to exercise programs is uncertain. The participants were not blinded, and the total duration of exercise was greater in the combined exercise training group than in the aerobic and resistance training groups. Either aerobic or resistance training alone improves glycemic control in type 2 diabetes, but the improvements are greatest with combined aerobic and resistance training. ClinicalTrials.gov registration number: NCT00195884.

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Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.

R Gryglewski, R M Palmer, S Moncada (1986)

Endothelium-derived vascular relaxing factor (EDRF) is a humoral agent that is released by vascular endothelium and mediates vasodilator responses induced by various substances including acetylcholine and bradykinin. EDRF is very unstable, with a half-life of between 6 and 50 s, and is clearly distinguishable from prostacyclin. The chemical structure of EDRF is unknown but it has been suggested that it is either a hydroperoxy- or free radical-derivative of arachidonic acid or an unstable aldehyde, ketone or lactone. We have examined the role of superoxide anion (O-2) in the inactivation of EDRF released from vascular endothelial cells cultured on microcarrier beads and bioassayed using a cascade of superfused aortic smooth muscle strips. With this system, we have now demonstrated that EDRF is protected from breakdown by superoxide dismutase (SOD) and Cu2+, but not by catalase, and is inactivated by Fe2+. These findings indicate that O-2 contributes significantly to the instability of EDRF.

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Endothelial dysfunction in diabetes mellitus

Hadi Hadi, Jassim Suwaidi (2007)

Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. A number of trials have demonstrated that statins therapy as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes. In the present review we provide the up to date details on this subject.

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Author and article information

Contributors

Massimo Federici: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 28 December 2012

Volume: 7

Issue: 12

Electronic Location Identifier: e53318

Affiliations

[1 ]Department of Physical Education, Institute of Bioscience, University of São Paulo State (UNESP), Rio Claro, São Paulo, Brazil

[2 ]Department of Anatomy, Cellular Biology, Physiology and Biophysics, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

[3 ]Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, São Paulo, Brazil

[4 ]Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

University of Tor Vergata, Italy

Author notes

* E-mail: azanesco@ 123456rc.unesp.br

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: MAD AZ. Performed the experiments: MAD APCD GKC GGA. Analyzed the data: MAD LVR EA AZ. Contributed reagents/materials/analysis tools: MAD APCD GKC GGA LVR EA AZ. Wrote the paper: MAD APCD GKC LVR EA AZ.

Article

Publisher ID: PONE-D-12-09090

DOI: 10.1371/journal.pone.0053318

PMC ID: 3532341

PubMed ID: 23285277

SO-VID: cccc3160-94fb-42dd-a85d-2e150d823a1a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 29 March 2012

Date accepted : 29 November 2012

Page count

Pages: 15

Funding

This work was funded by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo-FAPESP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Interaction between Advanced Glycation End Products Formation and Vascular Responses in Femoral and Coronary Arteries from Exercised Diabetic Rats

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Abstract

Background

Methodology/Principal Findings

Conclusion

Related collections

PLOS Climate

Most cited references 59

Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial.

Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.

Endothelial dysfunction in diabetes mellitus

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