Inhibition of plasminogen activator inhibitor-1 expression in vascular smooth muscle cells by protoporphyrins through a heme oxygenase-independent mechanism

    Authors

    X. L. Long;A. I. Schafer

    Comments

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    Abbreviated Journal Title

    Mol. Cell. Biochem.

    Keywords

    plasminogen activator inhibitor-1; heme oxygenase; TGF beta 1; protoporphyrin; vascular smooth muscle cells; GROWTH-FACTOR-BETA; CARBON-MONOXIDE; COBALT-PROTOPORPHYRIN; MYOCARDIAL-INFARCTION; FIBRINOLYTIC SYSTEM; ZINC PROTOPORPHYRIN; EPITHELIAL-CELLS; BALLOON INJURY; RISK-FACTOR; GENE; Cell Biology

    Abstract

    Heme oxygenase-1 (HO-1), a rate-limiting enzyme in heme catabolism, has been shown to play a regulatory role in the expression of plasminogen activator inhibitor-1 (PAI-1), a risk factor for vascular disease. Accordingly, we examined the effect of protoporphyrins, both HO inhibitors and activators, on PAI-1 expression in human vascular smooth muscle cells (VSMCs). Tin-protoporphyrin (SnPP) markedly inhibited the transforming growth factor beta 1 (TGF beta 1)-induced expression of PAI-1 protein. Protoporphyrins, whether they are inhibitors or activators of HO, produced a similar inhibitory effect. However, SnPP had no effect on the level of PAI-1 mRNA transcripts. Knockdown of human HO-1 with a specific siRNA did not reduce the PAI-1 protein level in TGF beta 1-treated cells. In addition, the proteasome inhibitor lactacystin reversed the inhibitory effect of SnPP on PAI-1 protein expression. Both cobalt-protoporphyrin (CoPP) and CoCl(2) markedly induced HO-1 expression. However, CoPP did not affect PAI-1 gene expression, whereas CoCl(2) upregulated PAI-1 mRNA in a dose-dependent manner. Our results demonstrate that protoporphyrins can block the TGF beta 1-mediated induction of PAI-1 protein in VSMCs and that this inhibitory effect is independent of HO activity.

    Journal Title

    Molecular and Cellular Biochemistry

    Volume

    312

    Issue/Number

    1-2

    Publication Date

    1-1-2008

    Document Type

    Article

    Language

    English

    First Page

    93

    Last Page

    101

    WOS Identifier

    WOS:000254905700011

    ISSN

    0300-8177

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