Resistencia a la insulina

Atherosclerosis 179 (2005) 43–49

Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat
Sandrine Delbosca , Eleni Paizanisb , Richard Magousb , Caroline Araiza , Th´ ophile Dimob , e a,∗ , Gerard Crosb , Jacqueline Azayb Jean-Paul Cristol
b a Laboratoire de Nutrition Humaine etAth´ rog´ n` se, Institut Universitaire de Recherche Clinique, 34093 Montpellier, France e e e Laboratoire de Pharmacologie et Physiopathologie Exp´ rimentales, INSERM U376, Facult´ de pharmacie, 34093 Montpellier-Cedex 5, France e e

Received 17 June 2004; received in revised form 19 October 2004; accepted 21 October 2004 Available online 10 December 2004

Abstract Growing evidences suggest arole of oxidative stress in hypertension and cardiac hypertrophy. The fructose (60%)-fed rat represents a model of metabolic syndrome, associating insulin resistance and high blood pressure. In this model, hypertension, cardiac and vessels hypertrophy and markers of oxidative stress were determined. In addition, the production of reactive oxygen species (ROS) was evaluated at different times afterthe initiation of fructose-enriched diet in aorta, heart and polymorphonuclear cells. High fructose feeding was associated with an early (1-week) increase in ROS production by aorta, heart and circulatory polymorphonuclear cells, in association with enhanced markers of oxidative stress. Vascular and cardiac hypertrophy was also rapidly observed, while the rise in blood pressure was significant onlyafter 3 weeks. In summary, our study suggests that the production of reactive oxygen species can be a key-event in the initiation and development of cardiovascular complications associated with insulin resistance. © 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Oxidative stress; NADPH oxidase; Insulin-resistance; Cardiovascular remodeling; Hypertension; Fructose-fed rat

1.Introduction There are considerable evidences suggesting that insulin resistance is associated with the development of cardiovascular diseases including atherosclerosis and hypertension [1,2]. Recently, the role of oxidative stress in the development of atherosclerosis in the insulin resistance syndrome (IRS) has been evoked [3]. Major components of IRS (insulin resistance, hypertension, dyslipidemia)generate oxidative stress in response to an overproduction of superoxide anion by the activation of NADPH oxidase. Recently, Inoguchi et al. [4]
∗ Corresponding author. Present address: Biochemistry Laboratory, Hˆ pital Lapeyronie, 371 Av. Doyen Gaston Giraud, 34295 Montpellier cedex o 5, France. Tel.: +33 4 67 33 83 45; fax: +33 4 67 33 83 93. E-mail address: jp-cristol@chu-montpellier.fr (J.-P.Cristol).

showed that free fatty acids (FFA) and elevated concentrations of glucose, were able to activate the NADPH oxidase from vascular (endothelial and smooth muscle) cells in a PKc-dependant mechanism. Similarly, Advanced Glycation End products (AGEs) resulting from interactions between glycation and oxidation, induced free radicals production through receptor-dependant NADPH oxidaseactivation [5]. Hypertension per se, is also associated to NADPH oxidase activation. Many studies on animal models of hypertension including angiotensin II-induced hypertension [6,7], DOCASalt hypertensive rat [8], spontaneous hypertensive rat (SHR) [9] and clinical studies [10] have shown an overproduction of reactive oxygen species. Moreover, the inhibition of NADPH by apocynin or the inactivation ofsuperoxide anion by scavengers (tempol) lowers elevated blood pressure [8,11].

0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.10.018

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S. Delbosc et al. / Atherosclerosis 179 (2005) 43–49

High-fructose feeding promotes insulin resistance by alterations of enzymes that regulate hepatic carbohydrates metabolism,...