Affiliations: [a] Department of Neurosurgery, Qilu Hospital of Shandong University, Ji'nan, China | [b] Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
Correspondence:
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Correspondence to: Teng Chen, Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wen Hua XI Road, Ji'nan 250012, China. Tel.: +86 531 82169116; Fax: +86 531 82169033; E-mail: chenteng2232@hotmail.com.
Abstract: Endothelial dysfunction and disruption of the blood-brain barrier have been found to be associated with Parkinson's disease (PD). However, the mechanisms underlying these effects have yet to be elucidated. It has also been found that activated protein C (APC) displays neuroprotective properties. Presently, the effects of APC on PD remain unknown. Using a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxin rodent model of PD, we found that administration of MPTP can reduce expression of endothelial protein C receptor (EPCR), an N-glycosylated type I membrane protein that has the ability to enhance protein C activation. However, the use of MPTP does not alter levels of thrombomodulin. These findings were verified in an in vitro study showing that 1-methyl-4-phenylpyridinium (MPP+) treatment leads to suppression of EPCR along with reduction of protein C activation in human primary endothelial cells. Importantly, our results display that activation of the transcriptional factor SP1 is involved in the inhibitory effects of MPTP/MPP+ on EPCR expression. We found that using 300 nM of the SP1 inhibitor MIT can abolish the effects of MPP+ on EPCR expression. Consistently, SP1 silencing using small RNA interference was able to prevent the inhibitory effects of MPTP/MPP+ on the reduction of EPCR expression and impairment of protein C activation. Importantly, our results indicate that overexpression of SP1 inhibits EPCR promoter activity. Our study suggests that EPCR-APC may be a potential therapeutic target for endothelial dysfunction in PD.
Keywords: Endothelial protein C receptor, MPTP/MPP+, Parkinson's disease, protein C, SP1
