AT1 blockade decreases NADPH oxidase 2 content and increases insulin signaling in a model of insulin resistance

Abstract

Angiotensin II (Ang II) increases oxidant production through the activation of Nox2 during insulin resistance (IR). Angiotensin receptor blockers (ARB) improve IR in the peripheral tissue suggesting a link among Ang II receptor (AT1) activation, oxidative stress and development of IR; however, these relationships in the heart are not well described. To test the hypothesis that AT1 activation increases NADPH oxidase (Nox) content and oxidative damage, while impairing insulin signaling and antioxidant enzyme activities, we measured Nox2 and 4, insulin signaling proteins, oxidative damage and antioxidant enzyme activity in the heart of OLETF rats, a model of insulin resistance. After 6 wks of treatment, hearts were collected from 3 groups of rats: 1) lean‐strain controls (LETO), 2) OLETF (15 wks of age), and 3) OLETF + ARB. ARB treatment increased Akt (57%) and AMPK (27%) activation in the OLETF rats, as well as, recovery in the p85α and Glut4 content. Similarly, AT1 blockade decreased (33%) Nox2 content, and increased (36%) Nox4, associated with increased catalase (41%) and SOD (70%) activities. The results suggest that Nox2 activity is dependent on AT1 activation and promotes oxidative damage. Furthermore, the parallel increases in Nox4 and antioxidant enzyme activities in the heart suggest that Nox4 activation is important for signaling cardiac antioxidant enzyme activities to abate the Nox2‐induced damage.