Background: Macrophages regulate the inflammatory response and affect re-endothelialization. Inflammation and macrophages play important roles in promoting tissue repair, but p38α mitogen-activated protein kinase's role in re-endothelialization is unknown.
Methods And Results: Wire injuries of carotid arteries and Evans blue staining were performed in macrophage-specific p38α-knockout (p38αLysMCre) mice and control mice (p38α). Re-endothelialization of the carotid arteries at 3, 5 and 7 days was significantly promoted in p38αLysMCre mice. In vitro experiments indicated that both the proliferation and migration of endothelial cells were enhanced in conditioned medium from peritoneal macrophages of p38αLysMCre mice. Interleukin-6 (IL-6) level was decreased significantly in macrophages of p38αLysMCre mice and an IL-6-neutralizing antibody promoted endothelial cell migration in vitro and re-endothelialization in p38α mice in vivo. Phosphoproteomics revealed that the phosphorylation level of S544/T545/S549 sites in megakaryocytic leukemia 1 (MKL1) was decreased in p38αLysMCre mice. The mutation of either S544/S549 or T545/S549 sites could reduce the expression of IL-6 and the inhibition of MKL1 reduced the expression of IL-6 in vitro and promoted re-endothelialization in vivo.
Conclusion: p38α in macrophages aggravates injury of arteries by phosphorylating MKL1, and increasing IL-6 expression after vascular injury.
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| http://dx.doi.org/10.1016/j.redox.2020.101775 | DOI Listing |
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