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

J Clin Invest. 2009 Apr;119(4):886-98. doi: 10.1172/JCI37262. Epub 2009 Mar 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Apoptosis
  • Atherosclerosis / enzymology*
  • Atherosclerosis / pathology*
  • Endoplasmic Reticulum / metabolism
  • Female
  • Humans
  • In Vitro Techniques
  • Macrophages, Peritoneal / enzymology*
  • Macrophages, Peritoneal / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 14 / deficiency*
  • Mitogen-Activated Protein Kinase 14 / genetics
  • Models, Biological
  • Necrosis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Stress, Physiological


  • Apolipoproteins E
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 14