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F o c u s o n Va s c u l a r D i s e a s e

Atherosclerosis: current pathogenesis and therapeutic options
Christian Weber1–3 & Heidi Noels4
Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronicinflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growingunderstanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
Atherosclerosis givesrise to cerebrovascular disease and CAD through a slowly progressing lesion formation and luminal narrowing of arteries. Upon plaque rupture and thrombosis, these most common forms of cardiovascular disease manifest as acute coronary syndrome (ACS), myocardial infarction or stroke. The underlying pathology is characterized by a chronic inflammatory process of the arterial wall that occurs atpredilection sites with disturbed laminar flow, such as branch points1. It is initiated by endothelial dysfunction and structural alterations, including the absence of a confluent luminal elastin layer and the exposure of proteoglycans2, which permit subendothelial accumulation of low-density lipoprotein (LDL). Elevated levels of circulating cholesterol transported by apolipoprotein B100(ApoB100)-containing LDL promote atherosclerosis and cardiovascular disease3. ApoB100 binding to negatively charged extracellular matrix proteoglycans leads to retention of LDL particles in the intima, where they are susceptible to oxidative modification by reactive oxygen species or enzymes such as myeloperoxidase or lipoxygenases released from inflammatory cells. Oxidized lipids and LDL (oxLDL) trigger theexpression of adhesion molecules and the secretion of chemokines by endothelial cells, which, together with the deposition of platelet-derived chemokines, drive intimal immune cell infiltration. Early ‘fatty-streak’ lesions consist of T cells and monocyte-derived
for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. 2Munich Heart Alliance, Munich, Germany.3Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands. 4Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany. Correspondence should be addressed to C.W. ( Published online 7 November 2011; doi:10.1038/nm.2538

© 2011 Nature America, Inc. All rightsreserved.

macrophage-like foam cells loaded with lipids. Successive accumulation of apoptotic cells, debris and cholesterol crystals forms a necrotic core. Fibroatheromatous plaques are covered by a fibrous cap composed of collagen and smooth muscle cells (SMCs), which are replaced by macrophages in the thinning inflamed caps that are prone to rupture. The ‘shoulder’ regions are heavilyinfiltrated by T cells and mast cells, which produce enzymes and proinflammatory mediators, contributing to adventitial inflammation of advanced plaques4. Hypercholesterolemic apolipoprotein E–deficient (Apoe−/−) or LDL receptor–deficient (Ldlr−/−) mice are frequently used to study mechanisms of disease initiation and progression but are less suitable for investigations of advanced stages, such as...
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