Endothelial and Macrophage-Specific Deficiency of P38a MAPK Does Not Affect the Pathogenesis of 2/2 Atherosclerosis in ApoE Mice Rozina Kardakaris¤a, Ralph Gareus¤b, Sofia Xanthoulea¤c, Manolis Pasparakis* Centre for Molecular Medicine, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany Abstract Background: The p38a 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 p38a in atherosclerosis development, in Apolipoprotein E deficient (ApoE2/2) mice. Methodology/Principal Findings: ApoE2/2 mice with macrophage or endothelial cell-specific p38a deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38a-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38a ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38a did not affect atherosclerotic plaque development in ApoE2/2 mice. Conclusions: Although previous studies implicated p38a signaling in atherosclerosis, our in vivo experiments suggest that p38a function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice. Citation: Kardakaris R, Gareus R, Xanthoulea S, Pasparakis M (2011) Endothelial and Macrophage-Specific Deficiency of P38a MAPK Does Not Affect the Pathogenesis of Atherosclerosis in ApoE2/2 Mice. PLoS ONE 6(6): e21055. doi:10.1371/journal.pone.0021055 Editor: Carlo Gaetano, Istituto Dermopatico dell’Immacolata, Italy Received November 25, 2010; Accepted May 19, 2011; Published June 9, 2011 Copyright: 2011 Kardakaris et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Cologne Excellence Cluster in Cellular Stress Responses in Aging Associated Diseases (CECAD) and the European Union (IMDEMI, MRTN-CT-2004-005632) to MP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: pasparakis@uni-koeln.de ¤a Current address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America. ¤b Current address: TaconicArtemis GmbH, Cologne, Germany. ¤c Current address: Department of Surgery, Nutrition and Toxicology, Research Institute Maastrich, Maastricht University Medical Center, The Netherlands. Introduction Atherosclerosis is the primary underlying cause of cardiovascu- lar disease and the major cause of mortality in the western world today [1], [2]. Originally considered a primarily metabolic disorder, atherosclerosis is now recognised as a complex disease with a strong inflammatory component [3]. Upon exposure to oxidized lipids, vascular endothelial cells are activated to express chemotactic factors and adhesion molecules that are crucial for the recruitment of monocytes. The recruited monocytes migrate into the sub-endothelial space and differentiate into macrophages that phagocytose lipids to become ‘foam cells’. Accumulation of foam cells beneath the endothelium, accompanied by the infiltration of T cells, leads to the formation of the ‘fatty streak’, which can later on progress into advanced atherosclerotic plaques and their complications [4]. Foam cells eventually die by apoptosis within the lesions and their clearance by other phagocytes is important to prevent their secondary necrosis and the formation of a necrotic core [5]. The mechanisms that control the recruitment, retention and cell survival, as well as the clearance of apoptotic foam cells within the lesions, are crucial for the pathogenesis of atheroscle- rosis. Pro-inflammatory signalling pathways that are activated downstream of innate immune and cytokine receptors, including the NF-kB and Mitogen-Activated Protein Kinase (MAPK) cascades, control immune, inflammatory and cell death responses and have been implicated in the pathogenesis of atherosclerosis [6], [7], [8]. The p38 MAPK pathway is crucial for a wide range of biological processes, including cell cycle, cell differentiation and apoptosis and the expression of inflammatory cytokines and chemokines [9]. p38a, the most physiologically relevant isoform of p38 involved in inflammatory responses [10], [11], has been implicated in the development and progression of atherosclerosis. Various roles have been attributed to this kinase with respect to atherogenesis, including the regulation of scavenger receptor expression and oxidized low-density lipoprotein (oxLDL) uptake by macrophages PLoS ONE | www.plosone.org 1 June 2011 | Volume 6 | Issue 6 | e21055