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Thromb Haemost 2015; 114(03): 603-613
DOI: 10.1160/TH15-01-0013
Blood Cells, Inflammation and Infection
Schattauer GmbH

Cleaved high-molecular-weight kininogen inhibits neointima formation following vascular injury

Jan-Marcus Daniel
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
2   Department of Biochemistry, Medical School, Justus-Liebig-University Giessen, Giessen, Germany
,
Fabian Reich
3   Department of Cardiology and Angiology, University Hospital Giessen & Marburg, Giessen, Germany
,
Jochen Dutzmann
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Simona Weisheit
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Rebecca Teske
3   Department of Cardiology and Angiology, University Hospital Giessen & Marburg, Giessen, Germany
,
Dursun Gündüz
3   Department of Cardiology and Angiology, University Hospital Giessen & Marburg, Giessen, Germany
,
Johann Bauersachs
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Klaus T. Preissner
2   Department of Biochemistry, Medical School, Justus-Liebig-University Giessen, Giessen, Germany
,
Daniel G. Sedding
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
2   Department of Biochemistry, Medical School, Justus-Liebig-University Giessen, Giessen, Germany
› Author Affiliations
Further Information

Publication History

Received: 08 January 2015

Accepted after major revision: 07 April 2015

Publication Date:
01 December 2017 (online)

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Summary

Cleaved high-molecular-weight kininogen (HKa) or its peptide domain 5 (D5) alone exert anti-adhesive properties in vitro related to impeding integrin-mediated cellular interactions. However, the anti-adhesive effects of HKa in vivo remain elusive. In this study, we investigated the effects of HKa on leukocyte recruitment and neointima formation following wire-induced injury of the femoral artery in C57BL/6 mice. Local application of HKa significantly reduced the accumulation of monocytes and also reduced neointimal lesion size 14 days after injury. Moreover, C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein (eGFP) showed a significantly reduced accumulation of eGFP+-cells at the arterial injury site and decreased neointimal lesion size after local application of HKa or the polypeptide D5 alone. A differentiation of accumulating eGFP+-cells into highly specific smooth muscle cells (SMC) was not detected in any group. In contrast, application of HKa significantly reduced the proliferation of locally derived neointimal cells. In vitro, HKa and D5 potently inhibited the adhesion of SMC to vitronectin, thus impairing their proliferation, migration, and survival rates. In conclusion, application of HKa or D5 decreases the inflammatory response to vascular injury and exerts direct effects on SMC by impeding the binding of integrins to extracellular matrix components. Therefore, HKa and D5 may hold promise as novel therapeutic substances to prevent neointima formation.

Keywords

Cleaved high-molecular-weight kininogen (HKa) - cell adhesion - inflammation - smooth muscle cells - neointimal formation

 

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