Title
Macrophage deficiency of <tex>$p38\alpha$</tex> MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice Macrophage deficiency of <tex>$p38\alpha$</tex> MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
New York, N.Y. ,
Subject
Human medicine
Source (journal)
The journal of clinical investigation. - New York, N.Y., 1924, currens
Volume/pages
119(2009) :4 , p. 886-898
ISSN
0021-9738
1558-8238
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
ER stress occurs in macrophage-rich areas of advanced atherosclerotic lesions and contributes to macrophage apoptosis and subsequent plaque necrosis. Therefore, signaling pathways that alter ER stressinduced apoptosis may affect advanced atherosclerosis. Here we placed Apoe/ mice deficient in macrophage p38α MAPK on a Western diet and found that they had a marked increase in macrophage apoptosis and plaque necrosis. The macrophage p38αdeficient lesions also exhibited a significant reduction in collagen content and a marked thinning of the fibrous cap, which suggests that plaque progression was advanced in these mice. Consistent with our in vivo data, we found that ER stressinduced apoptosis in cultured primary mouse macrophages was markedly accelerated under conditions of p38 inhibition. Pharmacological inhibition or genetic ablation of p38 suppressed activation of Akt in cultured macrophages and in atherosclerotic lesions. In addition, inhibition of Akt enhanced ER stressinduced macrophage apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stressinduced apoptosis that occurred with p38 inhibition in cultured cells. Our results demonstrate that p38α MAPK may play a critical role in suppressing ER stressinduced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo.
E-info
https://repository.uantwerpen.be/docman/iruaauth/9c28a0/f67dcf55993.pdf