Abstract-Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. ⅐Ϫ in the vessel wall, and they are present in endothelial cells, smooth muscle cells, fibroblasts, and infiltrated monocytes/macrophages. 3,4 Protein kinase C (PKC)-dependent p47phox phosphorylation and translocation are major mechanisms involved in phagocytic NADPH oxidase activation. 3 Phagocytic NADPH oxidase is overactivated in essential hypertension. 5,6 Clinical studies have demonstrated that treatment with losartan improves endothelial function and decreases blood pressure through a reduction in oxidative stress. 7,8 Moreover, several experimental studies have demonstrated beneficial effects of losartan treatment on vascular alterations by blocking NADPH oxidase activation. 9 -12 Losartan is hepatically metabolized by the cytochrome-P450 pathway and exerts its antihypertensive actions predominantly by EXP3174, its main metabolite and the pharmacological blocker of the angiotensin II type 1 receptor (AT 1 R). 13,14 Interestingly, during losartan metabolism, the liver also produces the EXP3179 metabolite, which has no AT 1 R-blocking properties. 14,15 In recent years, several studies have reported that the EXP3179 metabolite exerts AT 1 Rindependent actions. [15][16][17][18] Krämer et al 15 demonstrated that EXP3179 mediates the anti-inflammatory properties of losartan by abolishing cyclooxygenase-2 upregulation. Furthermore, EXP3179 stimulates endothelial NO synthase and suppresses tumor necrosis factor-␣-induced apoptosis. 16 Schupp et al 17 have demonstrated that EXP3179 acts as a peroxisome proliferator-activated receptor-␥ agonist. Finally, the ability of EXP3179 to inhibit collagen-dependent platelet activation has also been described. 18 Therefore, we hypothesized that EXP3179 metabolite might inhibit NADPH oxidase in phagocytic cells by AT 1 R-

These findings show that phagocytic NADPH oxidase activity is increased in obesity and is related to preclinical atherosclerosis in this condition. We also suggest that hyperleptinemia may contribute to phagocytic NADPH oxidase overactivity in obesity.

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Insulin resistance is associated with phagocytic NADPH oxidase activation. This association results in the highest cardiovascular risk in MetS patients.

The objective of the present study was to analyse the influence of the ACE (angiotensin-converting enzyme) gene I/D (insertion/deletion) polymorphism on NADPH oxidase-dependent O(2)(*-) (superoxide radical) production, and to investigate the clinical implication of this association in hypertensive subjects. A case-control study was performed in a random sample of the general population composed of 189 normotensive subjects and 223 hypertensive subjects. The ACE polymorphism was determined by PCR. NADPH oxidase-dependent O(2)(*-) production was quantified in phagocytic cells by chemiluminescence. MMP-9 (matrix metalloproteinase-9), a marker of atherosclerosis previously reported to be associated with NADPH oxidase overactivity, was quantified by ELISA in plasma samples. The distribution of genotypes was in Hardy-Weinberg equilibrium. The I/D polymorphism was not associated with hypertension. NADPH oxidase-dependent O(2)(*-) production was significantly higher in D/D (deletion/deletion) than in I/I (insertion/insertion) and I/D, both in normotensive and hypertensive subjects. Interestingly, plasma levels of angiotensin II were significantly higher in D/D than in I/I and I/D, both in normotensive and hypertensive subjects. Plasma levels of MMP-9 and systolic blood pressure values were significantly higher in D/D than in I/I and I/D hypertensive subjects, whereas no differences were found among genotypes in normotensive subjects. Interestingly, NADPH oxidase-dependent O(2)(*-) production positively associated with plasma MMP-9 levels in hypertensive subjects, which remained significant after adjustment for age and gender. In conclusion, in the present study we have reported for the first time an association of the D/D genotype of the ACE I/D polymorphism with phagocytic NADPH oxidase-mediated O(2)(*-) overproduction. Within the group of hypertensive patients, D/D cases also associated with increased blood pressure values and with enhanced plasma levels of MMP-9.