Neuroserpin, a thrombolytic serine protease inhibitor (serpin), blocks transplant vasculopathy with associated modification of T-helper cell subsets

Ganesh Munuswamy-Ramanujam; Erbin Dai; Liying Liu; Mira Shnabel; Yun Ming Sun; Mee Bartee; David A. Lomas; Alexandra R. Lucas

doi:10.1160/TH09-07-0441

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 103(03): 545-555
DOI: 10.1160/TH09-07-0441

Theme Issue Article

Schattauer GmbH

Neuroserpin, a thrombolytic serine protease inhibitor (serpin), blocks transplant vasculopathy with associated modification of T-helper cell subsets

Ganesh Munuswamy-Ramanujam

¹Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA

²Division of Cardiovascular Medicine, Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA

³Robarts Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada

⁴Department of Microbiology and Immunology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

,

Erbin Dai

¹Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA

³Robarts Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada

,

Liying Liu

¹Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA

³Robarts Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada

,

Mira Shnabel

³Robarts Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada

⁴Department of Microbiology and Immunology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

,

Yun Ming Sun

³Robarts Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada

⁴Department of Microbiology and Immunology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

⁶Viron Therapeutics, Inc., London, Ontario, Canada

,

Mee Bartee

¹Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA

²Division of Cardiovascular Medicine, Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA

,

David A. Lomas

⁷Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

,

Alexandra R. Lucas

¹Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA

²Division of Cardiovascular Medicine, Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, USA

³Robarts Research Institute, Department of Medicine, University of Western Ontario, London, Ontario, Canada

⁴Department of Microbiology and Immunology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

⁵Division of Cardiology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

› Institutsangaben

Abstract

Summary

Thrombolytic serine proteases not only initiate fibrinolysis, but also are up-regulated in vascular disease and acute inflammatory responses. Although the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is considered a main regulator of thrombolysis, PAI-1 is also associated with vascular inflammation. The role of other serpins that target thrombolytic proteases, PAI-2, PAI-3, and neuroserpin (NSP), in vascular inflammation is, however, less well defined. NSP is a mammalian serpin that, similar to PAI-1, inhibits urokinase- and tissue-type plasminogen activators (uPA and tPA, respectively) and has been most closely associated with the nervous system, with a demonstrated protective role after cerebral infarction in mouse models. However, the role of NSP in systemic arterial inflammation and plaque growth is not known. Serp-1 is a myxoma viral serpin that also inhibits tPA and uPA, as well as additionally inhibiting plasmin and factor Xa (fXa). Serp-1 has proven highly potent anti-inflammatory and anti-atherogenic activity. Here we assess the effects of NSP treatment on plaque growth and T-helper (Th) lymphocyte activity in a mouse aortic allograft transplant model, with comparison to Serp-1. NSP and Serp-1 both significantly reduced plaque growth and T-cell invasion. T-bet (a Th1 differentiation marker) was significantly reduced in transplanted aorta with associated reductions in Th1 and Th17, but not Th2, in splenocytes. NSP had additional Th modifying activity in non-transplanted mice. In summary, this is the first report that NSP possesses anti-inflammatory activity in systemic arteries, modifying Th cell responses and significantly reducing plaque growth in mouse aortic allografts.

Keywords

Serpin - neuroserpin - T-helper lymphocyte - transplant vasculopathy - atherosclerosis

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Referenzen

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