Overexpression of Fibulin-5 Attenuates Ischemia/Reperfusion Injury After Middle Cerebral Artery Occlusion in Rats

• Published in: Molecular neurobiology 2016-07, Vol.53 (5), p.3154-3167
• Main Authors: Guo, Jia, Cheng, Chuang, Chen, Cindy Si, Xing, Xiangfeng, Xu, Guanghui, Feng, Jinzhou, Qin, Xinyue
• Format: Article
• Language: English
• Subjects: Adenoviridae - metabolism; Adenovirus; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Blood-Brain Barrier - ultrastructure; Brain - metabolism; Brain - pathology; Brain Edema - complications; Brain Edema - metabolism; Brain Edema - pathology; Calcium-Binding Proteins - metabolism; Caspase 3 - metabolism; Cell Biology; Endothelial Cells - metabolism; Extravasation of Diagnostic and Therapeutic Materials - complications; Extravasation of Diagnostic and Therapeutic Materials - pathology; Gene expression; HEK293 Cells; Humans; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Ischemia; Magnetic Resonance Imaging; Male; Matrix Metalloproteinase 9 - metabolism; Neurobiology; Neurology; Neurosciences; Occludin - metabolism; Phosphorylation; Proteolysis; Proto-Oncogene Proteins c-akt - metabolism; rac1 GTP-Binding Protein - metabolism; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Recombination, Genetic - genetics; Reperfusion Injury - etiology; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Rodents; Stroke - complications; Stroke - metabolism; Stroke - pathology; Superoxide Dismutase - metabolism; Veins & arteries
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-015-9222-2

Ischemia/reperfusion (I/R) injury after middle cerebral artery occlusion (MCAO) induces detrimental processes such as oxidative stress, inflammation, and apoptosis. All parts of the neurovascular unit are involved in these pathological processes. Fibulin-5 is a 66-kD glycoprotein secreted by various vascular cells, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. As an extracellular matrix protein involved in cell adhesion, fibulin-5 has been widely studied in tumor growth and invasion. However, the effects of fibulin-5 on brain injury following ischemia/reperfusion have not been reported. In this study, we examined the effect of overexpressed fibulin-5 on reactive oxygen species (ROS) production. Fibulin-5 overexpression attenuated ROS expression, which in turn decreased apoptosis and blood–brain barrier (BBB) permeability following MCAO and reperfusion. Fibulin-5 also improved neurological deficits but had no effect on infarction volume. T2-weighted MRI and electron microscopy further confirmed brain edema reduction and decreased BBB disruption in fibulin-5 overexpression recombinant adenovirus (Ad-FBLN) treated rats. In addition, tight junction protein occludin was significantly degraded and matrix metalloproteinase 9 (MMP-9) immunoreactivity was significantly increased. Fibulin-5-mediated ROS decrease was not due to increased total superoxide dismutase levels but was instead correlated with the activation of Rac-1 pathway. The findings highlight the importance of antioxidant mechanism underlying cerebral ischemia/reperfusion.