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

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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 β1 (TGFβ1)-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 TGFβ1-treated cells. In addition, the proteasome inhibitor lactacystin reversed the inhibitory effect of SnPP on PAI-1 protein expression. Both cobalt-protoporphyrin (CoPP) and CoCl2 markedly induced HO-1 expression. However, CoPP did not affect PAI-1 gene expression, whereas CoCl2 upregulated PAI-1 mRNA in a dose-dependent manner. Our results demonstrate that protoporphyrins can block the TGFβ1-mediated induction of PAI-1 protein in VSMCs and that this inhibitory effect is independent of HO activity.

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Acknowledgments

This work was supported by National Institutes of Health grant HL-36045 (to A.I. Schafer).

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Authors and Affiliations

  1. Biomolecular Science Center, University of Central Florida, 4000 Central Florida Blvd., BMSC, Bldg. 20, Room 133, Orlando, FL, 32816-2364, USA

    Xilin Long

  2. Department of Medicine, Weill Cornell Medical College, New York Presbyterian-Weill Cornell Medical Center, 525 East 68th Street, Box 130, New York, NY, 10021, USA

    Andrew I. Schafer

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  1. Xilin Long
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  2. Andrew I. Schafer
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Correspondence to Andrew I. Schafer.

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Long, X., Schafer, A.I. Inhibition of plasminogen activator inhibitor-1 expression in vascular smooth muscle cells by protoporphyrins through a heme oxygenase-independent mechanism. Mol Cell Biochem 312, 93–101 (2008). https://doi.org/10.1007/s11010-008-9724-6

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  • DOI: https://doi.org/10.1007/s11010-008-9724-6

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