Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice.
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 stress-induced apoptosis may affect advanced atherosclerosis. Here we placed Apoe-/- mice deficient in macrophage p38alpha MAPK on a Western diet and found that they had a marked increase in macrophage apoptosis and plaque necrosis. The macrophage p38alpha-deficient 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 stress-induced 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 stress-induced macrophage apoptosis, and expression of a constitutively active myristoylated Akt blocked the enhancement of ER stress-induced apoptosis that occurred with p38 inhibition in cultured cells. Our results demonstrate that p38alpha MAPK may play a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo.
Seimon
Tracie A
TA
Department of Medicine, Division of Molecular Medicine, Columbia University, PH 9-405, 630 W. 168th Street, New York, New York 10032, USA. tad2105@columbia.edu
Wang
Yibin
Y
Han
Seongah
S
Senokuchi
Takafumi
T
Schrijvers
Dorien M
DM
Kuriakose
George
G
Tall
Alan R
AR
Tabas
Ira A
IA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D008954:Models, Biological; D009336:Necrosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013312:Stress, Physiological
D001057:Apolipoproteins E; D051057:Proto-Oncogene Proteins c-akt; D048308:Mitogen-Activated Protein Kinase 14