Glucocorticoid and Cyclic Nucleotide Regulation of Plasminogen Activator and Plasminogen Activator-Inhibitor Gene Expression in Primary Cultures of Rat Hepatocytes

Abstract

Primary cultures of rat hepatocytes produce tissue-type plasminogen activator (tPA) and plasminogen activator-inhibitor type 1 (PAI-1). Incubation of hepatocytes with 50 microM 8-(4-chlorophenylthio)cAMP (CPT-cAMP) results in a 4-fold increase in tPA activity, whereas the synthetic glucocorticoid dexamethasone (1 microM) causes a more than 90% decrease. In combination, dexamethasone completely overcomes the CPT-cAMP effect and markedly decreases PA activity. PAI-1 is induced by both CPT-cAMP and dexamethasone, and the effects of these agents are additive. Accumulation of tPA mRNA is increased more than 4-fold by CPT-cAMP and is greatly decreased by incubation with dexamethasone. Dexamethasone in combination with CPT-cAMP totally blocks this cAMP effect. The protein synthesis inhibitor cycloheximide does not prevent either the dexamethasone-induced decrease or the CPT-cAMP-induced increase in tPA message and, in fact, augments the cAMP-induced increase in tPA mRNA. Hepatocyte PAI-1 mRNA levels are increased 2-fold by incubation with either CPT-cAMP or dexamethasone; in combination, these effectors cause a 4-fold increase in PAI-1 mRNA. Cycloheximide alone causes a marked increase in PAI-1 mRNA, but does not block the induction by either CPT-cAMP or dexamethasone. We conclude that incubation of hepatocytes with CPT-cAMP induces tPA activity by increasing tPA mRNA accumulation and that dexamethasone causes a decrease in tPA activity by both decreasing tPA mRNA and increasing PAI-1 mRNA and activity. Concomitant protein synthesis is not required for the regulation of tPA or PAI-1 mRNA by either CPT-cAMP or dexamethasone, indicating a primary effect of these agents on gene transcription or mRNA stability.

Transcriptional regulation of the rat tissue type plasminogen activator gene: localization of DNA elements and nuclear factors mediating constitutive and cyclic AMP-induced expression.

“…Many different cell types and tissues express tPA at variable levels, and often the expression is regulated by hormones and growth factors (23,46,53,62). In unstimulated rat granulosa cells, the level of tPA mRNA is low, but following FSH stimulation, the level is rapidly increased about 20-fold, after which there is a slow decrease to the level found in untreated cells (43,45).…”

Does Chronic Corticosteroid Use Increase Risks of Readmission, Thromboembolism, and Revision After THA?

“…Mechanistically, corticosteroids can decrease serum levels of cytokines that cause reactive inflammation and hypercoagulability in the immediate postoperative period [11,12,14,26]. However, corticosteroids also can increase the synthesis and release of clotting factors and fibrinolysis inhibitors, thereby enhancing coagulation [9,10,18]. Therefore, further study is indicated to explore the topic of thromboembolic events in chronic corticosteroid users.…”

Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1

“…PAI-1, as a member of the SERPIN (Serine Protease Inhibitor) family, is a single chain, 50-kDa glycoprotein that can be produced by platelets, vascular endothelial cells, vascular smooth muscle cells, and some other nonvascular cell types such as hepatocytes. [1][2][3] Moreover, a factor known as protein C inhibitor (PCI), which can be synthesized in liver and some other steroidresponsive organs, was proposed to be named PAI-3. 4 We and others have shown that PAI-1 gene expression can be induced by hypoxia via binding of the transcription factor hypoxiainducible factor-1 (HIF-1) to hypoxia response elements (HREs) in the PAI-1 gene promoter.…”