Extracts Enriched in Different Polyphenolic Families Normalize Increased Cardiac NADPH Oxidase Expression while Having Differential Effects on Insulin Resistance, Hypertension, and Cardiac Hypertrophy in High-Fructose-Fed Rats NAJIM A. AL-AWWADI, ² CAROLINE ARAIZ, ‡ AURE Ä LIE BORNET, § SANDRINE DELBOSC, ‡ JEAN-PAUL CRISTOL, ‡ NATHALIE LINCK, ² JACQUELINE AZAY, ² PIERRE-LOUIS TEISSEDRE,* ,§ AND GE Ä RARD CROS ² Laboratoire de Pharmacologie et Physiopathologie Expe ´rimentales, INSERM U376, 15 Av. Charles Flahault, B.P. 14491, 34093 Montpellier Cedex 5, France, Laboratoire de Nutrition Humaine et Athe ´roge ´ne `se, Institut Universitaire de Recherche Clinique, 34093 Montpellier Cedex 5, France, and Centre d’Oenologie, UMR 1083 Sciences pour l’Oenologie, Faculte ´ de Pharmacie, 15 Av. Charles Flahault, B.P. 14491, 34093 Montpellier Cedex 5, France Insulin resistance and oxidative stress act synergistically in the development of cardiovascular complications. The present study compared the efficacy of three polyphenolic extracts in their capacity to prevent hypertension, cardiac hypertrophy, increased production of reactive oxygen species (ROS) by the aorta or the heart, and increased expression of cardiac NAD(P)H oxidase in a model of insulin resistance. Rats were fed a 60%-enriched fructose food and were treated once a day (gavage) for 6 weeks with 10 mL/kg of water only (F group) or the same amount of solution containing a red grape skin polyphenolic extract enriched in anthocyanins (ANT), a grape seed extract enriched in procyanidins and rich in galloylated procyanidins (PRO), or the commercial preparation Vitaflavan (VIT), rich in catechin oligomers. All treatments were administered at the same dose of 21 mg/kg of polyphenols. Our data indicate that (a) the ANT treatment prevented hypertension, cardiac hypertrophy, and production of ROS, (b) the PRO treatment prevented insulin resistance, hypertriglyceridemia, and overproduction of ROS but had only minor effects on hypertension or hypertrophy, while (c) Vitaflavan prevented hypertension, cardiac hypertrophy, and overproduction of ROS. All polyphenolic treatments prevented the increased expression of the p91phox NADPH oxidase subunit. In summary, our study suggest that (a) the pathogeny of cardiac hypertrophy in the fructose-fed rat disease involves both hypertension and hyperproduction of ROS, (b) polyphenolic extracts enriched in different types of polyphenols possess differential effects on insulin resistance, hypertension, and cardiac hypertrophy, and (c) polyphenols modulate the expression of NAD(P)H oxidase. KEYWORDS: Polyphenols; tannins; anthocyanins; galloylated procyanidins; hypertension; cardiac hypertrophy; oxidative stress; NADPH oxidase; insulin resistance INTRODUCTION Feeding rats with fructose has been reported to generate many metabolic features of syndrome X or metabolic syndrome (1), which associates glucose intolerance, visceral obesity, hyperten- sion, insulin resistance, and dyslipidemia, and predisposes to type II diabetes development and atherosclerotic cardiovascular disease (2-4). The involvement of oxidative stress in the murine model was suggested by an increase in lipid peroxides and decrease in free radical defense mechanisms (5, 6). We previously showed that high fructose feeding was associated with a precocious increase in ROS production by aorta, heart, and polynuclear cells as well as moderate hypertension and cardiac hypertrophy after 1 week of diet only. Cardiac hyper- trophy was strongly correlated with cardiac superoxide anion production, suggesting that reactive oxygen species (ROS) could be a key event in cardiovascular complications of insulin resistance. Giving some antioxidants molecules could therefore decrease the insulin resistance-related oxidative stress and the subsequent hypertension, as antioxidants such as vitamin E have been shown to improve the free radical defense system and subsequently the insulin sensitivity in fructose fed rats (5). Polyphenols are natural compounds found in most vegetables and fruits and are responsible for their taste and pigmentation. * Author to whom correspondence should be addressed [telephone 33 (0)4 67 54 86 74; fax 33 (0)4 67 54 86 86; e-mail teissed@univ-montp1.fr]. ² Laboratoire de Pharmacologie et Physiopathologie Expe ´rimentales. ‡ Institut Universitaire de Recherche Clinique. § Centre d’Oenologie. J. Agric. Food Chem. 2005, 53, 151-157 151 10.1021/jf048919f CCC: $30.25 © 2005 American Chemical Society Published on Web 12/13/2004