The angiotensin-converting enzyme insertion/deletion polymorphism is associated with phagocytic NADPH oxidase-dependent superoxide generation: potential implication in hypertension

Abstract

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.

The Future Challenge of Reactive Oxygen Species (ROS) in Hypertension: From Bench to Bed Side

“…Additionally, the ROS production-mediated expression of pro-inflammatory gene products [ 116 ] and the modulation of the early signal transduction pathways that are involved in the control of cell growth and death have been reported to contribute to hypertension-induced tissue damage [ 116 , 117 ]. Clinical studies have also demonstrated that patients with hypertension produced excessive amounts of ROS, exhibited higher levels of plasma H 2 O 2 than normotensive subjects [ 16 , 118 , 119 , 120 ] and are characterized by unbalanced levels of antioxidant defense mechanisms [ 121 ]. This implies that oxidative signaling pathways are attractive targets with which to prevent the development of hypertension and possibly its complications [ 122 , 123 ].…”

“…Moreover, we must also keep in mind the fact that the role of oxidative stress in priming hypertension in humans is still debated, even if oxidative stress biomarkers positively correlate with blood pressure in essential hypertension [ 32 , 41 , 78 , 108 , 119 ] and circulating SOD was recently found to be a marker of cardiovascular alterations in hypertensive and diabetic patients [ 164 ]. Our laboratory has recently found that the naturally occurring unacylated form of ghrelin (UnAG) is a potent antioxidant compound, which acts on both progenitors and mature endothelial cells.…”

Alcoholic lung injury: Metabolic, biochemical and immunological aspects

“…An association of the D/D genotype of the angiotensin converting enzyme ( ACE) I/D polymorphism with phagocytic NADPH oxidase-mediated superoxide overproduction has been reported (Jose et al, 2009). The observation suggests that the mechanisms that control the angiotensin pathway are linked to the development of oxidative stress and potentially oxidative injury.…”