Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury
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Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury. / Kapopara, Piyushkumar R; von Felden, J; Soehnlein, Oliver; Wang, Y; Napp, L Christian; Sonnenschein, K; Wollert, Kai C; Schieffer, Bernhard; Gaestel, Matthias; Bauersachs, Johann; Bavendiek, Udo.
In: THROMB HAEMOSTASIS, Vol. 112, No. 6, 12.2014, p. 1264-76.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury
AU - Kapopara, Piyushkumar R
AU - von Felden, J
AU - Soehnlein, Oliver
AU - Wang, Y
AU - Napp, L Christian
AU - Sonnenschein, K
AU - Wollert, Kai C
AU - Schieffer, Bernhard
AU - Gaestel, Matthias
AU - Bauersachs, Johann
AU - Bavendiek, Udo
PY - 2014/12
Y1 - 2014/12
N2 - 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 re-endothelialisation. Therefore, we investigated the role of MK2 in remodelling and re-endothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-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 re-endothelialisation 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.
AB - 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 re-endothelialisation. Therefore, we investigated the role of MK2 in remodelling and re-endothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-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 re-endothelialisation 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.
KW - Animals
KW - Carotid Artery Injuries
KW - Carotid Artery, Common
KW - Cell Adhesion
KW - Cell Movement
KW - Cell Proliferation
KW - Cells, Cultured
KW - Chemokine CCL2
KW - Chemokine CCL5
KW - Disease Models, Animal
KW - Endothelium, Vascular
KW - Hypercholesterolemia
KW - Hyperplasia
KW - Inflammation
KW - Intracellular Signaling Peptides and Proteins
KW - Leukocytes
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Muscle, Smooth, Vascular
KW - Myocytes, Smooth Muscle
KW - Neointima
KW - Protein-Serine-Threonine Kinases
KW - Re-Epithelialization
KW - Receptors, LDL
KW - Vascular Remodeling
KW - Wound Healing
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1160/TH14-02-0174
DO - 10.1160/TH14-02-0174
M3 - SCORING: Journal article
C2 - 25120198
VL - 112
SP - 1264
EP - 1276
JO - THROMB HAEMOSTASIS
JF - THROMB HAEMOSTASIS
SN - 0340-6245
IS - 6
ER -
