Reciprocal Effects of Oxidative Stress on Heme Oxygenase Expression and Activity Contributes to Reno-Vascular Abnormalities in EC-SOD Knockout Mice

Tomoko Kawakami,Toru Takahashi,Nader G Abraham,Rita Rezzani,Kiyoshi Morita,Tim D Oury,Lars Bellner,Komal Sodhi,Nitin Puri

doi:10.1155/2012/740203

Abstract

Heme oxygenase (HO) system is one of the key regulators of cellular redox homeostasis which responds to oxidative stress (ROS) via HO-1 induction. However, recent reports have suggested an inhibitory effect of ROS on HO activity. In light of these conflicting reports, this study was designed to evaluate effects of chronic oxidative stress on HO system and its role in contributing towards patho-physiological abnormalities observed in extracellular superoxide dismutase (EC-SOD, SOD3) KO animals. Experiments were performed in WT and EC-SOD(−/−) mice treated with and without HO inducer, cobalt protoporphyrin (CoPP). EC-SOD(−/−) mice exhibited oxidative stress, renal histopathological abnormalities, elevated blood pressure, impaired endothelial function, reduced p-eNOS, p-AKT and increased HO-1 expression; although, HO activity was significantly (P < 0.05) attenuated along with attenuation of serum adiponectin and vascular epoxide levels (P < 0.05). CoPP, in EC-SOD(−/−) mice, enhanced HO activity (P < 0.05) and reversed aforementioned pathophysiological abnormalities along with restoration of vascular EET, p-eNOS, p-AKT and serum adiponectin levels in these animals. Taken together our results implicate a causative role of insufficient activation of heme-HO-adiponectin system in pathophysiological abnormalities observed in animal models of chronic oxidative stress such as EC-SOD(−/−) mice.

Highlights

Oxidative stress induces NRF2-dependent antioxidant enzymes including the heme-Heme oxygenase (HO) system [1], whose two isoforms HO-1 and HO-2 catabolizes free heme to equimolar concentrations of biliverdin (BV), carbon monoxide (CO), and iron
The present study demonstrates that chronic oxidative stress, as seen in EC-superoxide dismutases (SOD)(−/−) mice, has reciprocal effects on HO expression and activity and that pharmacological induction of HO restores redox homeostasis and reverts pathophysiological abnormalities observed in these animals
These effects of HO induction are associated with concomitant increases in epoxide and adiponectin levels, which may contribute towards the HO-induced reversal of renovascular abnormalities in EC-SOD(−/−) mice

Summary

Introduction

Oxidative stress induces NRF2-dependent antioxidant enzymes including the heme-HO system [1], whose two isoforms HO-1 (inducible) and HO-2 (constitutive) catabolizes free heme to equimolar concentrations of biliverdin (BV), carbon monoxide (CO), and iron. Apart from inducible NRF2-dependent genes, constitutive enzymes such as superoxide dismutases (SOD) regulate basal redox and prevent excess-free radical accumulation. Gene deletion of EC-SOD results in chronic oxidative stress, endothelial dysfunction, and increased blood pressure [17, 19, 20], implicating this enzyme in the regulation of redox homeostasis and preservation of cardiovascular and renal function. Induction of HO1 in SOD3-deficient mice restored HO activity and redox homeostasis, and prevented renovascular injury and offset endothelial dysfunction and elevated blood pressure. These events are accompanied by the restoration of vascular epoxide and serum adiponectin levels with a concomitant increase in p-AKT and p-eNOS expression

Research Design and Methods

Results

Discussion