Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 61
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Cellular Mechanisms of Diabetic Vasculopathy

C. Peiró and C.F. Sánchez-Ferrer

Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain

It is well known that long-term diabetes mellitus leads to a high incidence of vascular diseases such as atherosclerosis, myocardial infarction or hypertension (1). Diabetic vessels initially undergo functional alterations that are later followed by structural changes, including remodeling processes, as observed in both experimental models or human patients (2, 3).

Among the causes leading to such vascular complications, a growing body of evidence has pointed to oxidative stress as a pivotal factor (4). Indeed, diabetic vessels exhibit a prooxidant status, which may be the consequence of reduced antioxidant defenses and/or increased production of different reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide or hydroxyl radicals (4).

Supporting this evidence, ROS have emerged in recent years as key mediators in cell signaling (5). In the vasculature, ROS have been shown to regulate the activation of different signal transduction pathways, and they seem to be involved in the different processes, such as cell growth or apoptosis, which contribute to vessel structure design (5). At the nuclear level, ROS can modulate the expression of a certain number of redox-regulated genes in vascular cells, among which AP-1 and NF-kB are probably the best characterized (6). Both AP-1 and NF-kB have been involved in vascular remodeling (6). In addition, NF-kB closely regulates the expression of many genes, including proinflammatoy cytokines, chemokines or adhesion molecules, and it appears to be overexpressed in several human diseases, particularly those characterized by a chronic inflammatory state, including diabetes mellitus (7).

In diabetic vessels, hyperglycemia can directly contribute to the formation of ROS, but it can also facilitate the formation of other ROS-releasing compounds through nonenzymatic glycosylation processes. Indeed, glucose and reactive protein amino groups can undergo a condensation reaction, yielding Schiff bases that rearrange in Amadori adducts within days or weeks, which can, in turn, undergo irreversible changes to form the so-called advanced glycosylation end-products (AGEs) after longer periods of time (6). Although several studies have focused on the possible role of AGEs in diabetic vascular remodeling, to date, little work has been performed to analyze the possible participation of Amadori adducts, which are in fact the prominent form of circulating glycated proteins in vivo.

Previous work from our group has provided evidence that human oxyhemoglobin, taken as a representative Amadori adduct, impairs endothelium-dependent relaxations in human mesenteric microvessels by releasing ROS (8). We further propose that Amadori adducts directly influence vascular remodeling in diabetes through the activation of redox-dependent signaling pathways in vascular cells.

REFERENCES

1. Stamler, J. et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993, 16: 434-44.

2. Rumble, J.R. et al.Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products. J Clin Invest 1997, 99: 1016-27.

3. Giannattasio, C. et al. Progression of large artery structural and functional alterations in Type I diabetes. Diabetologia 2001, 44:
203-8.

4. Giugliano, D. et al. Oxidative stress and diabetic vascular complications. Diabetes Care 1996, 19: 257-67.

5. Irani, K. Oxidant signaling in vascular cell growth, death, and survival: A review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res 2000, 87: 179-83.

6. Kunsch, C., Medford, R.M. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res 1999, 85: 753-66.

7. Barnes, P., Karin, M. Nuclear factor-kB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997, 336: 1066-71.

8. Vallejo, S. et al. Highly glycated oxyhaemoglobin impairs nitric oxide relaxations in human mesenteric microvessels. Diabetologia 2000, 43: 83-90.

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 61
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com