Heme oxygenase-1 expression is down-regulated by angiotensin II and under hypertension in human neutrophils

Abstract

Angiotensin II (Ang II) is a peptide hormone able to elicit a strong production of reactive oxygen species by human neutrophils. In this work, we have addressed whether expression of heme oxygenase-1 (HO-1), an antioxidant enzyme, becomes altered in these cells upon Ang II treatment or under hypertension conditions. In neutrophils from healthy and hypertensive subjects, induction of HO-1 mRNA and protein expression with a parallel increase in enzyme activity took place upon treatment with 15-deoxy-Delta12,14-PGJ2 (15dPGJ2). However, Ang II prevented HO-1 synthesis by normal neutrophils in vitro, and HO-1 expression was depressed in neutrophils from hypertensive patients in comparison with cells from healthy subjects. In addition, Ang II treatment led to a reduced HO-1 enzyme activity to levels similar to those found in neutrophils from hypertensive patients. NO donors reversed the inhibition of 15dPGJ2-dependent HO-1 expression in neutrophils from hypertensive patients, and conversely, inhibition of inducible NO synthase (NOS2) activity counteracted the stimulatory effect of 15dPGJ2 on HO-1 expression in normal human neutrophils. Moreover, Ang II canceled 15dPGJ2-dependent induction of NOS2 mRNA synthesis. Present findings indicate that down-regulation of HO-1 expression in neutrophils from hypertensive subjects is likely exerted through the inhibition of NOS2 expression. Additionally, they underscore the potential usefulness of NO donors as new, therapeutic agents against hypertension.

Biochemical and genetic alterations of oxidant/antioxidant status of the brain in rats treated with dexamethasone: protective roles of melatonin and acetyl-l-carnitine

“…It was stated that MEL-and ALC-induced neuroprotective activity is mediated via the potentiation of other brain antioxidants (e.g., GST-P1, ascorbic acid, and other, yet unidentified, compounds) that, by altering the cell's redox state, they could attenuate the subsequent activation of NF-κB and AP-1. Indeed, the induction of HO-1 expression is a NO-dependent process [5], and the significant inhibition of NOS-1 and NOS-2 mRNA expression given by MEL and ALC may be inhibition of the gene expression of HO-1 and HO-2 as indicated in the current study.…”

Calcineurin expression and activity is regulated by the intracellular redox status and under hypertension in human neutrophils

“…Our group has previously shown that HO1 synthesis is induced by 15dPGJ 2 in neutrophils, and that HO1 expression (at the mRNA and protein levels) and activity are downregulated in both neutrophils from healthy subjects treated with Ang II and in untreated neutrophils from hypertensive patients (Alba et al 2008). As Ang II is able to induce both CN synthesis and activity in human neutrophils, we have examined in this work the possibility that the Ang II effect observed on HO1 might be mediated by CN.…”

“…In a previous work, we found that Ang II treatment before 15dPGJ 2 addition significantly prevented nuclear accumulation of Nrf2 (Alba et al 2008). We have now studied the possible participation of CN in NRF2 expression.…”

“…So, it is currently considered as a crucial enzyme to counteract intracellular oxidative stress. We have recently described that HO1 mRNA and protein expression becomes reduced together with its enzyme activity in human normal neutrophils on their treatment with Ang II (Alba et al 2008). In this work, we set to investigate whether the downmodulatory action of Ang II on HO1 expression was mediated by CN.…”

“…In neutrophils from healthy and hypertensive subjects, we have reported that expression of the antioxidant enzyme hemoxygenase-1 (HO1 (HMOX1)) becomes induced at the mRNA and protein levels with a parallel increase in enzyme activity on treatment with prostaglandin (Alba et al 2008). The present work focuses on the role that an altered intracellular redox status plays in the induction of CN activity.…”