Induction of Plasminogen Activator Inhibitor Type 1 Synthesis by Cadmium in Human Vascular Endothelial Cells in Culture.

Abstract

Cadmium is a unique heavy metal that stimulates the secretion of plasminogen activator inhibitor type 1 (PAI-1) from vascular endothelial cells. However, it has been incompletely understood whether cadmium stimulation of PAI-1 secretion actually results in a reduction of endothelial fibrinolytic activity and whether the stimulation results from an induction of endothelial PAI-1 synthesis. To address these questions, human umbilical vein endothelial cells were cultured with cadmium chloride in the presence or absence of actinomycin D, H-7 or HA1004. The activity of tissue type and urokinase type plasminogen activators (t-PA and u-PA, respectively) in the conditioned medium was analyzed by fibrin zymography and mRNAs coding t-PA, u-PA and PAI-1 were determined by quantitative reverse transcription-polymerase chain reaction. Results of the experiments indicate that cadmium reduces the activity of both t-PA and u-PA in vascular endothelial cells through induction of PAI-1 synthesis which is mediated by protein kinase C activation. Since the PAI-1 induction by cadmium was observed in neither human vascular smooth muscle cells nor human fibroblasts, it was suggested that vascular endothelial cells are a particular cell type of which PAI-1 synthesis is stimulated by cadmium.

Proteoglycans Predominantly Synthesized by Human Brain Microvascular Endothelial Cells in Culture are Perlecan and Biglycan

“…Nolan and Shaikh 25) suggested that the initial effect of acute cadmium administration is on the integrity and permeability of the vascular endothelium and other necrotic changes in the underlying tissue occur secondarily. We have shown that cadmium, 26,27) lead, [27][28][29] arsenite, 30) and the biologically active sulfated polysaccharide sodium spirulan [31][32][33] influence the functions, including proteoglycan metabolism, of vascular endothelial cells. Proteoglycans are involved in the regulation of vascular endothelial cell functions; however, excluding a few exceptions such as the inhibition of vascular endothelial repair by lead, the toxicity or biological activity that mediate altered proteoglycan metabolism has not been completely understood.…”

Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells

“…Because cadmium exposure is a risk factor for atherosclerosis (Houtman, 1993;Fagerberg et al, 2012), we previously studied the cytotoxicity of cadmium in vascular endothelial cells using a cell culture system. Our analyses showed that vascular endothelial cells are sensitive to cadmium cytotoxicity (Kaji et al, 1996); cadmium influences the synthesis of heparan sulfate proteoglycans (Ohkawara et al, 1997) and lowers fibrinolytic activity by promoting the synthesis and secretion of plasminogen activator inhibitor-1 (Yamamoto et al, 1993;Yamamoto and Kaji, 2002). Endothelial cells can be protected from cadmium cytotoxicity by zinc (Kaji et al, 1992;Mishima et al, 1997).…”

The effect of cadmium on the coagulation and fibrinolytic system in women with uterine endometrial cancer and myoma

“…PAI-1 and PAI-2 act as primary inhibitors of these proteins. Research conducted by Yamamoto and Kaji [48] indicates that cadmium reduces the activity of both t-PA and u-PA in vascular endothelial cells through induction of PAI-1 synthesis, which is mediated by protein kinase C activation. However, in our study, increases in PAI-1 concentration were only observed in the groups of females with endometrial cancer.…”