Effects of cadmium on the release of tissue plasminogen activator and plasminogen activator inhibitor type 1 from cultured human vascular smooth muscle cells and fibroblasts

Yamamoto, Chika; Kaji, Tatsuru; Sakamoto, Michiko; Kono, Hiroshi

doi:10.1016/0300-483x(95)03184-h

Cited by 19 publications

(20 citation statements)

References 27 publications

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“…37) On the other hand, cadmium and lead show different effects on the secretion of fibrinolytic proteins in vascular smooth muscle cells and fibroblasts. 39,40) Thus, it is suggested that the effects of heavy metals on the synthesis and secretion of fibrinolytic proteins depend on either the kind of metal or the cell type, although the mechanisms are unclear. The present data support the concept that cadmium is a particular heavy metal that induces PAI-1 synthesis in vascular endothelial cells, and that the cells are a particular type of which PAI-1 synthesis is induced by cadmium.…”

Section: Discussionmentioning

confidence: 99%

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

Yamamoto

Kaji

2002

JOURNAL OF HEALTH SCIENCE

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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.

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Section: Discussionmentioning

confidence: 99%

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

Yamamoto

Kaji

2002

JOURNAL OF HEALTH SCIENCE

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“…8,9 Previous reports have indicated that metallothionein is not well induced in smooth muscle cells compared with endothelial cells or fibroblasts, and this may result in a heightened sensitivity of cultured smooth muscle cells to cadmium toxicity. 3,10 In the presence of cadmium accumulation, similar mechanisms could be important in fully understanding how smoking damages the vasculature. …”

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“…There are reports that cadmium alters the metabolism of cultured human aortic smooth muscle cells and the processing of collagen. 2,3 Cadmium also blocks calcium channels and inhibits ATPases and other ion transport systems.…”

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Cadmium Accumulation in Aortas of Smokers

Abu‐Hayyeh

Sian

Jones

et al. 2001

ATVB

107

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Abstract-Abdominal aortic aneurysm is a smoking-related disorder. Cadmium, inhaled from cigarettes, may accumulate in the aorta and facilitate weakening of the aorta through adverse effects on smooth muscle cell metabolism. Cadmium was measured by atomic absorption spectrometry in infrarenal aortas from 13 patients with abdominal aortic aneurysm and from 17 age-and sex-matched patients with normal-diameter abdominal aorta. Total cadmium content was associated with smoking, assessed as pack-years (rϭ0.54, Pϭ0.004), but was similar in aneurysmal and undilated aortas. The cadmium content (meanϮSE) was higher in the media (3.25Ϯ0.53 ng/mg dry wt, 7Ϯ1.2 mol/L) than in the intima or adventitia (1.14Ϯ0.24 and 1.87Ϯ0.38 ng/mg dry wt, respectively; ANOVA, PϽ0.005). There was a strong correlation between medial cadmium content and pack-years of smoking (rϭ0.87, PϽ0.001). In aortic smooth muscle cells cultured on fibrillar collagen, cadmium inhibited DNA synthesis and collagen synthesis and diminished cell numbers (IC 50 2 mol/L, 6 mol/L, and 6 mol/L, respectively), but higher concentrations of cadmium were required for upregulation of metallothionein (EC 50 23 mol/L). The cadmium content of the aorta increases in direct proportion to the pack-years of cigarettes smoked, with selective accumulation in the medial layer. However, the cadmium content of aneurysmal aortas was not higher than that of nondilated aortas for patients with matched smoking history. In smokers, the level of cadmium accumulation is probably sufficient to impair the viability of cultured smooth muscle cells. Similar mechanisms could underlie the development of degenerative aortic disease in smokers. Key Words: aortas Ⅲ aneurysm Ⅲ smoking Ⅲ muscle smooth Ⅲ collagen C admium is one of the many toxic components of inhaled tobacco smoke. The amount of cadmium inhaled from each pack of 20 cigarettes is Ϸ16 g. 1 Cadmium has a long elimination time (estimated at 10 to 30 years), providing the possibility for the accumulation of substantial amounts of cadmium during the lifetime of a smoker. There are reports that cadmium alters the metabolism of cultured human aortic smooth muscle cells and the processing of collagen. 2,3 Cadmium also blocks calcium channels and inhibits ATPases and other ion transport systems.Smoking is the most consistent risk factor for the development and expansion of abdominal aortic aneurysms (AAAs). 4,5 The histological features of AAA include atherosclerosis, loss of medial smooth muscle (with evidence of apoptosis), and loss of elastin (with remodeling of the connective tissue). Therefore, we wished to investigate the hypothesis that cadmium, from cigarettes, accumulates in the infrarenal abdominal aorta, thus stimulating aneurysmal dilatation. To test this hypothesis, we compared the concentration of cadmium in infrarenal aortas from patients with and without AAAs.After finding that the highest concentration of cadmium was in the medial layer of the aorta, we investigated whether similar concentrations of cadmium altered the metabol...

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“…In experimental studies, it has been shown that temporary and rapid leucocytosis occurs after cadmium administration [17] . There are reports proposing that cadmium toxicity may affect vascular endothelial cells, vascular smooth muscle cells and thrombocytes [18][19][20][21][22][23] .…”

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The Effects of Chronic Cadmium Toxicity on the Hemostatic System

Koçak

Akçıl²

2006

Pathophysiol Haemos Thromb

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Cadmium, a highly toxic heavy metal, is distributed widely in the general environment. The characteristic clinical manifestations of chronic cadmium intoxication include renal proximal tubular dysfunction, osteomalacia and anemia. Accumulating evidence suggests that cadmium toxicity may also affect various organs such as the liver, lung, testis and hematopoietic system. The aim of this study was to determine the effect of chronic cadmium exposure on the anticoagulant system in rats. Fourty-five adult Wistar albino rats were randomly allocated into 2 groups. While the control group was given tap water, the animals in the cadmium group were treated with 15 ppm CdCl₂ for 4 weeks. Blood cadmium concentration, prothrombin time, activated partial thromboplastin time, plasma protein C and antithrombin activity, and platelet count were determined in the rats. Blood cadmium concentrations increased in the experiment group compared to the control group (p < 0.001). Results also show that cadmium exposure shortened prothrombin time (p < 0.05) and activated partial thromboplastin time (p < 0.01) in rats. Protein C (p < 0.001) and antithrombin (p < 0.001) decreased to statistically significantly lower levels in rat plasma after cadmium exposure when compared to the control group. When the number of thrombocytes was compared between 2 groups, a decrease was observed in the group treated with CdCl₂, which was, however, not statistically significant (p > 0.05). In conclusion, when the parameters of the hemolytic system are considered, the decrease in protein C and antithrombin activities and the shortening of prothrombin time and activated partial thromboplastin time suggests the presence of a hypercoagulable state during chronic cadmium intoxication. Therefore, it may be stated that chronic cadmium toxicity sets the stage for hypercoagulation and hence increases the risk of thrombosis.

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Effects of cadmium on the release of tissue plasminogen activator and plasminogen activator inhibitor type 1 from cultured human vascular smooth muscle cells and fibroblasts

Cited by 19 publications

References 27 publications

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

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

Cadmium Accumulation in Aortas of Smokers

The Effects of Chronic Cadmium Toxicity on the Hemostatic System

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