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

Hyun      Joo Jung; Mei      Zi Yang; Ki      Hyo Kwon; Midori      A. Yenari; Yoon      Jung Choi; Won      Taek Lee; Kyung      Ah Park; Jong      Eun Lee

Abstract

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 (ADCΔbEnd.3 cells). The ADCΔbEnd.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 ADCΔbEnd.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 ADCΔbEnd.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 ADCΔbEnd.3 cells. Moreover, the expression of activating transcription factor 3 (ATF3) was increased significantly in ADCΔbEnd.3 cells. In addition, the suppression of the MMP-2 and MMP-9 expression in ADCΔbEnd.3 cells was prevented with ATF3 small interfering RNA (siRNA) treatment. These results suggest that the endogenous agmatine in ADCΔbEnd.3 cells inhibits the MMPs expression mediated via the regulation of eNOS, NO and ATF3.

Keywords: Arginine decarboxylase, agmatine, activating transcription factor 3, endothelial cell, matrix metalloproteinases, endothelial nitric oxide synthase

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