Grape-Derived Polyphenols Prevent Doxorubicin-Induced Blunted EDH-Mediated Relaxations in the Rat Mesenteric Artery: Role of ROS and Angiotensin II

Noureddine Idris-Khodja,Paola Di Marco,Valérie B Schini-Kerth,Mona Farhat,Bernard Geny

doi:10.1155/2013/516017

Abstract

This study determined whether doxorubicin, an anticancer agent, impairs endothelium-dependent relaxations mediated by nitric oxide (NO) and endothelium-derived hyperpolarization (EDH) in the mesenteric artery and, if so, the mechanism underlying the protective effect of red wine polyphenols (RWPs), a rich natural source of antioxidants. Male Wistar rats were assigned into 4 groups: control, RWPs, doxorubicin, and doxorubicin + RWPs. Vascular reactivity was assessed in organ chambers; the vascular formation of reactive oxygen species (ROS) using dihydroethidine and the expression levels of small and intermediate conductance calcium-activated potassium channels (SKCa, IKCa) and connexin 40 (Cx40), which are involved in EDH-type relaxations, endothelial NO synthase (eNOS), angiotensin II, and AT1 receptors by immunofluorescence. The doxorubicin treatment impaired EDH-mediated relaxations, whereas those mediated by NO were minimally affected. This effect was associated with reduced expression levels of SKCa, IKCa, and Cx40, increased expression levels of eNOS, angiotensin II, and AT1 receptors, and formation of ROS in mesenteric arteries. RWPs prevented both the doxorubicin-induced blunted EDH-type relaxations and the increased vascular oxidative stress, and they improved the expression levels of target proteins. These findings suggest that polyphenol-rich natural products might be of interest in the management of doxorubicin-induced vascular injury possibly by improving the vascular angiotensin system.

Highlights

Doxorubicin is a highly effective anticancer agent with a broad spectrum of activity in human cancers, which is often used for the treatment of solid tumors and malignant hematological diseases [1]
This study determined whether doxorubicin, an anticancer agent, impairs endothelium-dependent relaxations mediated by nitric oxide (NO) and endothelium-derived hyperpolarization (EDH) in the mesenteric artery and, if so, the mechanism underlying the protective effect of red wine polyphenols (RWPs), a rich natural source of antioxidants
Vascular reactivity was assessed in organ chambers; the vascular formation of reactive oxygen species (ROS) using dihydroethidine and the expression levels of small and intermediate conductance calciumactivated potassium channels (SKCa, IKCa) and connexin 40 (Cx40), which are involved in EDH-type relaxations, endothelial NO synthase, angiotensin II, and AT1 receptors by immunofluorescence

Summary

Introduction

Doxorubicin is a highly effective anticancer agent with a broad spectrum of activity in human cancers, which is often used for the treatment of solid tumors and malignant hematological diseases [1]. A major limitation of doxorubicin treatment is its dose-dependent cardiotoxicity [2]. Doxorubicin has been shown to induce oxidative stress which can lead to dilated cardiomyopathy with the subsequent development of left ventricular dysfunction and congestive heart failure [3]. Doxorubicin appears to impair the vascular function by inducing an endothelial dysfunction [4, 5]. The endothelium plays a major role in vascular homeostasis mostly by generating the formation of nitric oxide (NO), a potent vasodilator synthesized by endothelial NO synthase (eNOS) [6,7,8,9], and by inducing endotheliumdependent hyperpolarization- (EDH-) mediated relaxations [10]. The EDH component of endothelium-dependent relaxations increases as the size of the artery decreases [11] and innevlsol(vsemsatlhl eanadctiinvtaetriomnedoifateencdoonthdeulciatal nScKeCCa aa2n+d-acIKtivCaatecdhaKn+-

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