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

Piyushkumar R. Kapopara; Johann von Felden; Oliver Soehnlein; Yong Wang; L. Christian Napp; Kristina Sonnenschein; Kai C. Wollert; Bernhard Schieffer; Matthias Gaestel; Johann Bauersachs; Udo Bavendiek

doi:10.1160/th14-02-0174

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

²Hannover Biomedical Research School, Hannover Medical School, Hannover, Germany

,

Johann von Felden

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

Oliver Soehnlein

³Institute for Cardiovascular Prevention, Ludwig-Maximilians University, Munich, Germany

⁴Academic Medical Center, Department of Pathology, Amsterdam University, the Netherlands

⁵DZHK (German Centre for Cardiovascular Research), and partner site Munich Heart Alliance, Germany

,

Yong Wang

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

L. Christian Napp

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

Kristina Sonnenschein

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

Kai C. Wollert

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

Bernhard Schieffer

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

Matthias Gaestel

⁶Department of Biochemistry, Hannover Medical School, Hannover, Germany

,

Johann Bauersachs

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

,

Udo Bavendiek

¹Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

› Author Affiliations

Abstract

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

Full Text

References

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