Endogenous Agmatine Inhibits Cerebral Vascular Matrix Metalloproteinases Expression by Regulating Activating Transcription Factor 3 and Endothelial Nitric Oxide Synthesis

• DOI: 10.2174/156720210792231804
• Publication Date: 2010-08-14T09:25:29Z
• Authors: Hyun Joo Jung; Mei Zi Yang; Ki Hyo Kwon; Midori A. Yenari; Yoon Jung Choi; Won Taek Lee; Kyung Ah Park; Jong Eun Lee
• Keywords: 0301 basic medicine; Agmatine; Nitric Oxide Synthase Type III; Cells; Activating Transcription Factor 3/metabolism*; Blotting, Western; 610; Nitric Oxide; Transfection; Brain/blood supply; Cell Line; Mice; 03 medical and health sciences; Animals; Endothelium; agmatine; Cells, Cultured; Chromatography, High Pressure Liquid; Nitric Oxide/biosynthesis*; Chromatography; endothelial nitric oxide synthase; Analysis of Variance; 0303 health sciences; Cultured; Activating Transcription Factor 3; Blotting; Reverse Transcriptase Polymerase Chain Reaction; Vascular/metabolism*; Nitric Oxide Synthase Type III/metabolism; matrix metalloproteinases; Brain; Agmatine/metabolism*; Brain/metabolism*; Immunohistochemistry; Matrix Metalloproteinases/genetics; Matrix Metalloproteinases; Arginine decarboxylase; Activating Transcription Factor 3/genetics; High Pressure Liquid; Nitric Oxide Synthase Type III/genetics; endothelial cell; Matrix Metalloproteinases/metabolism*; Endothelium, Vascular; Nitric Oxide/genetics; Western; activating transcription factor 3

Earlier investigations from our laboratory demonstrated that the expression of matrix metalloproteinases (MMPs) was down-regulated by exogenously administered agmatine against ischemia-like injuries in the murine brain capillary endothelial (bEnd.3) cells. In our present study, we intended to investigate the mechanism involved in the inhibition of MMPs in bEnd.3 cells infected with retroviral containing human arginine decarboxylase (hADC) gene which can synthesize agmatine endogenously (ADCDeltabEnd.3 cells). The ADCDeltabEnd.3 cells were subjected to oxygen glucose deprivation (OGD, 6 hrs) with reperfusion (18 hrs). High performance liquid chromatography (HPLC) analysis revealed the high levels of agmatine in the ADCDeltabEnd.3 cells compared to other experimental groups. The results demonstrated significant decrease in cell death and increase in the nitric oxide (NO) production in the ADCDeltabEnd.3 cells. The increased expression of MMP-2 and MMP-9, and decreased expression of endothelial nitric oxide synthase (eNOS) by ischemic injury was attenuated in ADCDeltabEnd.3 cells. Moreover, the expression of activating transcription factor 3 (ATF3) was increased significantly in ADCDeltabEnd.3 cells. In addition, the suppression of the MMP-2 and MMP-9 expression in ADCDeltabEnd.3 cells was prevented with ATF3 small interfering RNA (siRNA) treatment. These results suggest that the endogenous agmatine in ADCDeltabEnd.3 cells inhibits the MMPs expression mediated via the regulation of eNOS, NO and ATF3.