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Thromb Haemost 2014; 112(06): 1264-1276
DOI: 10.1160/th14-02-0174
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury

Piyushkumar R. Kapopara
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
2   Hannover Biomedical Research School, Hannover Medical School, Hannover, Germany
,
Johann von Felden
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Oliver Soehnlein
3   Institute for Cardiovascular Prevention, Ludwig-Maximilians University, Munich, Germany
4   Academic Medical Center, Department of Pathology, Amsterdam University, the Netherlands
5   DZHK (German Centre for Cardiovascular Research), and partner site Munich Heart Alliance, Germany
,
Yong Wang
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
L. Christian Napp
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Kristina Sonnenschein
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Kai C. Wollert
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Bernhard Schieffer
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Matthias Gaestel
6   Department of Biochemistry, Hannover Medical School, Hannover, Germany
,
Johann Bauersachs
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
,
Udo Bavendiek
1   Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
› Institutsangaben Financial support: This work was supported by the ADUMED-foundation and the German Heart Research Foundation (grant DSHF F/05/10) to U. B.; and by the DFG (SO876/3–1, SO876/6–1, SFB1123 TP A06 & TP B05) and the NWO (VIDI project 91712303) to O. S.
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Publikationsverlauf

Received: 26. Februar 2014

Accepted after major revision: 30. Juni 2014

Publikationsdatum:
29. November 2017 (online)

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Summary

Maladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and reendothelialisation. Therefore, we investigated the role of MK2 in remodelling and reendothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-densitylipoprotein- receptor-deficient mice (ldlr-/- ) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/- ) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved reendothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty.

Keywords

Arterial remodelling - reendothelialisation - MK2 - inflammation - leukocytes

 

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