%0 Journal Article
%T Role of Matrix Metalloproteinase Activity in the Neurovascular Protective Effects of Angiotensin Antagonism
%A Tauheed Ishrat
%A Anna Kozak
%A Ahmed Alhusban
%A Bindu Pillai
%A Maribeth H. Johnson
%A Azza B. El-Remessy
%A Adviye Ergul
%A Susan C. Fagan
%J Stroke Research and Treatment
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/560491
%X Background and Purpose. Oxidative stress and matrix metalloproteinase (MMP) activity have been identified as key mediators of early vascular damage after ischemic stroke. Somewhat surprisingly, the angiotensin II type 1 receptor (AT1) blocker, candesartan, has been shown to acutely increase MMP activity while providing neurovascular protection. We aimed to determine the contribution of MMP and nitrative stress to the effects of angiotensin blockade in experimental stroke. Methods. Wistar rats (n£¿=£¿9¨C14/group; a total of 99) were treated in a factorial design with candesartan 1£¿mg/kg IV, alone or in combination with either a peroxynitrite decomposition catalyst, FeTPPs, 30£¿mg/kg IP or GM6001 50£¿mg/kg IP (MMP inhibitor). Neurological deficit, infarct, size and hemorrhagic transformation (HT) were measured after 3£¿h of middle cerebral artery occlusion (MCAO) and 21£¿h of reperfusion. MMP activity and nitrotyrosine expression were also measured. Results. Candesartan reduced infarct size and HT when administered alone ( ) and in combination with FeTPPs ( ). GM6001 did not significantly affect HT when administered alone, but the combination with candesartan caused increased HT ( ) and worsened neurologic score ( ). Conclusions. Acute administration of candesartan reduces injury after stroke despite increasing MMP activity, likely by an antioxidant mechanism. 1. Introduction Ischemic stroke, an obstruction of blood flow in a major cerebral vessel, remains a leading cause of adult disability and death in the United States [1]. Because of its complex pathology, a major research and clinical priority is to develop therapeutic interventions in the ischemic brain through the understanding of underlying mechanisms. Ischemia reperfusion leads to a cascade of pathophysiological processes, resulting in further brain damage. Accumulations of free radicals, oxygen/nitrogen species (ROS/RNS), not only increase the susceptibility of brain tissue to reperfusion-induced damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death [2, 3]. As an important component of free radicals, RNS, including peroxynitrite (ONOO¨C), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia reperfusion results in the production of peroxynitrite in ischemic brain, which triggers numerous molecular cascades and leads to vascular damage. In vitro, peroxynitrite strongly activates matrix metalloproteinases (MMPs) [4, 5]. Peroxynitrite formation on
%U http://www.hindawi.com/journals/srt/2014/560491/