Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice

Tracie A Seimon ¹, Yibin Wang , Seongah Han

⁰Department of Medicine, Division of Molecular Medicine, Columbia University, PH 9-405, 630 W. 168th Street, New York, New York 10032, USA. tad2105@columbia.edu

The Journal of Clinical Investigation +

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March 17, 2009

View abstract on PubMed

Summary

Macrophage p38alpha MAPK suppresses ER stress-induced apoptosis, crucial for advanced atherosclerosis. Its deficiency accelerates macrophage death and plaque necrosis, highlighting its protective role in atherosclerotic lesions.

Area Of Science

Cardiovascular Biology
Cellular Stress Response
Atherosclerosis Research

Background

Endoplasmic reticulum (ER) stress in macrophages promotes atherosclerotic plaque necrosis.
Signaling pathways modulating ER stress-induced apoptosis are critical in advanced atherosclerosis.

Purpose Of The Study

To investigate the role of macrophage p38alpha MAPK in ER stress-induced apoptosis within atherosclerotic lesions.
To elucidate the signaling mechanisms linking p38alpha MAPK, Akt, and ER stress in macrophages.

Main Methods

Apoe-/- mice lacking macrophage p38alpha MAPK were fed a Western diet.
Macrophage apoptosis and atherosclerotic lesion characteristics were analyzed.
In vitro studies used cultured macrophages with p38 or Akt inhibition/activation.

Main Results

Macrophage p38alpha deficiency increased apoptosis and plaque necrosis in vivo.
Lesions showed reduced collagen and thinner fibrous caps, indicating advanced plaque progression.
p38 inhibition accelerated ER stress-induced apoptosis in cultured macrophages.
p38 inhibition suppressed Akt activation; Akt inhibition enhanced ER stress-induced apoptosis.

Conclusions

p38alpha MAPK plays a vital role in suppressing ER stress-induced macrophage apoptosis.
This suppression occurs both in vitro and in advanced atherosclerotic lesions in vivo.
The p38alpha-Akt pathway is a key regulator of macrophage apoptosis in atherosclerosis.

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