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Am J Physiol Heart Circ Physiol. 2020 Jan 31. doi: 10.1152/ajpheart.00280.2019. [Epub ahead of print]

Antithrombotic Effects of Heme-Degrading and Heme-Binding Proteins.

Author information

1
Nephrology and Hypertension, Mayo Clinic, United States.
2
Department of Laboratory Medicine and Pathology, Mayo Clinic, United States.
3
Division of Hematology, Oncology and Transplantation, University of Minnesota, United States.
4
Nephrology and Hypertension, Mayo Clinic College of Medicine, United States.
5
Division of Infectious Diseases, Mayo Clinic, United States.
6
Laboratory Medicine & Pathology; Nephrology and Hypertension, Mayo Clinic, United States.
7
Department of Emergency Medicine, University of Maryland School of Medicine, United States.
8
Department of Medicine, University of Minnesota Med School, United States.

Abstract

In the murine venous thrombosis model induced by ligation of the inferior vena cava (IVCL), genetic deficiency of heme oxygenase-1 (HO-1) increases clot size. This study examined whether induction of HO-1 or administration of its products reduces thrombosis. Venous HO-1 upregulation by gene delivery reduced clot size, as did products of HO activity, biliverdin and carbon monoxide. Induction of HO-1 by hemin reduced clot formation, clot size, and upregulation of PAI-1 that occurs in the IVCL model, while leaving uPA and tPA expression unaltered. The reductive effect of hemin on clot size required HO activity. The IVCL model exhibited relatively high concentrations of heme which peaked just prior to maximum clot size, then declined as clot size decreased. Administration of hemin decreased heme concentration in the IVCL model. HO-2 mRNA was induced 2-fold in the IVCL model (versus 40-fold HO-1 induction), but clot size was not increased in HO-2-/- mice compared with HO-2+/+ mice. Hemopexin, the major heme-binding protein, was induced in the IVCL model, and clot size was increased in hemopexin-/- mice compared with hemopexin+/+ mice. We conclude that in the IVCL model the heme-degrading protein, HO-1, and HO products inhibit thrombus formation, as does the heme-binding protein, hemopexin. The reductive effects of hemin administration require HO activity and are mediated, in part, by reducing PAI-1 upregulation in the IVCL model. We speculate that HO-1, HO, and hemopexin reduce clot size by restraining the increase in clot concentration of heme (now recognized as a procoagulant) that otherwise occurs.

KEYWORDS:

bile pigments; carbon monoxide; heme oxygenase-1; hemopexin; venous thromboembolic disease

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