Endothelial and Macrophage-Specific Deficiency of P38[alpha] MAPK Does Not Affect the Pathogenesis of Atherosclerosis in ApoE.sup.-/- Mice

The p38[alpha] Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38[alpha] in atherosclerosis development, in Apolipoprotein E deficient (ApoE.sup.-/-) mice. ApoE.sup.-/- mice with macrophage or endothelial cell-specific p38[alpha] deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38[alpha]-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38[alpha] ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38[alpha] did not affect atherosclerotic plaque development in ApoE.sup.-/- mice. Although previous studies implicated p38[alpha] signaling in atherosclerosis, our in vivo experiments suggest that p38[alpha] function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice.