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Basic science
Improving the treatment of atherosclerosis by linking anti-inflammatory and lipid modulating strategies
  1. Alma Zernecke1,
  2. Christian Weber2,3
  1. 1Rudolf Virchow-Center/DFG-Research Center for Experimental Medicine, University of Würzburg, Würzburg, Germany
  2. 2Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU) Munich, Munich Heart Alliance, München, Germany
  3. 3Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
  1. Correspondence to Professor Dr Christian Weber, Institute for Cardiovascular Prevention (IPEK), Pettenkoferstr. 9, München 80336, Germany; christian.weber{at}med.uni-muenchen.de

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Atherosclerotic vascular disease manifests as a progressive narrowing of the vessel wall, and underlies coronary artery disease (CAD) and cerebrovascular disease. With consequences such as myocardial infarction and stroke, atherosclerosis remains the most frequent cause of death in the western world. While a strong heritable component is undisputed, the molecular inflammatory and immune mechanisms in the evolution of the disease are still not fully understood. By using both animal models of disease (foremost genetically manipulated mice) as well as human tissue, and more recently by employing unbiased approaches to discover genetic loci predisposing to disease development, investigators have revealed a complex picture of multilayered cellular processes and molecular mechanisms. Here we highlight the current view on atherosclerosis and provide an updated account of the critical factors involved in disease development, as illustrated by various prototypic examples.

In brief, the response-to-injury hypothesis of Russell Ross introduced the notion that monocyte―endothelial interactions give rise to foam cells and growth factor induced smooth muscle cell (SMC) proliferation, triggering lesion formation.1 Our understanding of the atherogenic process has been considerably refined by the appreciation of subendothelial ApoB lipoprotein retention containing low density lipoprotein (LDL) in the vessel wall under conditions of elevated concentrations of circulating cholesterol. This may predominantly occur at predilection sites with disturbed flow, for example, at branch points of vessels, where increased endothelial turnover and structural changes in elastins and proteoglycans occur, which permit subendothelial accumulation of LDL. In the intima, LDL particles are prone to modifications by reactive oxygen species or enzymes such as myeloperoxidase or lipoxygenases released from inflammatory cells. These oxidised lipids (oxLDL) further trigger the expression of adhesion molecules which contribute to intimal leucocyte recruitment. While early ‘fatty streak’ lesions mostly comprise lipid laden, monocyte derived, macrophage-like foam …

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