Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
Tracie A. Seimon, … , Alan R. Tall, Ira A. Tabas
Tracie A. Seimon, … , Alan R. Tall, Ira A. Tabas
Published March 16, 2009
Citation Information: J Clin Invest. 2009;119(4):886-898. https://doi.org/10.1172/JCI37262.
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Research Article Cardiology

Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice

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 stress–induced 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 p38α–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 p38α MAPK may play a critical role in suppressing ER stress–induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo.

Authors

Tracie A. Seimon, Yibin Wang, Seongah Han, Takafumi Senokuchi, Dorien M. Schrijvers, George Kuriakose, Alan R. Tall, Ira A. Tabas

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Figure 6

Inhibition of p38α MAPK accelerates macrophage apoptosis during ER stress.

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Inhibition of p38α MAPK accelerates macrophage apoptosis during ER stres...
(A) p38afl/flApoe–/– and p38afl/flLysMCre+/–Apoe–/– peritoneal macrophages were left untreated (Un), treated with acetyl-LDL (AcLDL), cholesterol-loaded (acetyl-LDL plus 58035; FC loading) for 16–18 h, or treated with 5 μg/ml tunicamycin (Tn) for 24 h, after which cells were assayed for apoptosis. Data are expressed as the percent of total cells that stained with annexin V and propidium iodide. (B) Cells as in A were untreated or treated with 2 μM thapsigargin (Thaps) or 5 μg/ml tunicamycin for 24 h, then assayed as in A. (C and D) Wild-type mouse peritoneal (C) or human monocyte–derived (D) macrophages were pretreated with 10 μM SB202190 (SB) or the vehicle DMSO control for 1 h and then treated with 5 μg/ml tunicamycin or 0.25 μM thapsigargin (C) or with 0.25 μM thapsigargin or 0.25 μM thapsigargin plus acetyl-LDL (D) for 24 h and assayed for apoptosis as described in A. In A–D, common symbols denote differences that are not statistically significant (P > 0.05), while different symbols denote statistically significant differences (P < 0.05); ANOVA with Student-Newman-Keuls post-test. (E–G) Peritoneal macrophages were pretreated for 1 h with 10 μM SB202190 or the vehicle DMSO control. Cells were then given 20 μg/ml 7-ketocholesterol or serum starved for 18 h (E), treated with 100 nM staurosporine (STS) for 24 h (F), or UV irradiated and followed for 7 h (G). Cells were then assayed for apoptosis as described in A. All data are mean ± SEM (n = 4). In E–G, *P < 0.05, ANOVA with Student-Newman-Keuls post-test.