DIPYRIDAMOLE 抑制人類腹膜表面細胞增生之作用機轉
Date Issued
2000
Date
2000
Author(s)
蔡敦仁
DOI
892314B002059
Abstract
Proliferation of human peritoneal mesothelial cells (HPMC) accompanied by collagen
synthesis is regarded as the main process predisposing to peritoneal fibrosis (PF) in patients of
long-term continuous ambulatory peritoneal dialysis (CAPD). However, the precise molecular
mechanism regulating HPMC proliferation has never been reported. We previously had
reported that dipyridamole (DP) is potential as an antiproliferative and antifibrotic agent. We
thus investigated the mechanism and effect of dipyridamole in regulation of HPMC proliferation.
HPMC was cultured from human omentum by an enzyme digestion method. Cell
proliferation was measured by methyltetrazolium assay. Intracellular cAMP was measured
using an enzyme immunoassay kit. Cell-cycle distribution of HPMC was analyzed by flow
cytometry. Expressions of cell-cycle proteins (Cyclin D1, CDK4, pRB and p27 kip1 ) were determined by Western blotting. Addition of DP suppressed PDGF-stimulated HPMC proliferation by cell-cycle arrest at G1
phase. The antimitogenic effect of DP was mediated predominantly through the cAMP
pathway. PDGF induced elevated protein levels of cyclin D1 but the CDK4 protein level did
not change. Dipyridamole and DBcAMP had no effect on levels of cyclin D1 and CDK4 in
PDGF-stimulated HPMC. PDGF decreased p27 kip1 and induced pRB phosphorylation of
HPMC. In contrast, dipyridamole attenuated PDGF-stimulated pRB phosphorylation by
preventing p27 kip1 degradation. Dipyridamole appears to inhibit PDGF-stimulated HPMC proliferation through increased
cAMP, preservation of p27 kip1 and decreased pRb phosphorylation. Our study of dipyridamole
may provide a therapeutic basis for clinical applications in the prevention of PF.
Subjects
continuous ambulatory peritoneal dialysis
fibrosis
cell-cycle
dipyridamole
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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