title: Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies.
abstract: Understanding the pathophysiology of atherogenesis and the progression of atherosclerosis have been major goals of cardiovascular research during the previous decades. However, the complex molecular and cellular mechanisms underlying plaque destabilization remain largely obscure. Here, we review how lesional cells undergo cell death and how failed clearance exacerbates necrotic core formation. Advanced atherosclerotic lesions are further weakened by the pronounced local activity of matrix-degrading proteases as well as immature neovessels sprouting into the lesion. To stimulate translation of the current knowledge of molecular mechanisms of plaque destabilization into clinical studies, we further summarize available animal models of plaque destabilization. Based on the molecular mechanisms leading to plaque instability, we outline the current status of clinical and preclinical trials to induce plaque stability with a focus on induction of dead cell clearance, inhibition of protease activity, and dampening of inflammatory cell recruitment.
authors.affiliation: From the Departments of Pathology (C.S.-R., M.D., O.S.) and Biochemistry (C.S.-R., M.d.W., E.L.), Academic Medical Center, Amsterdam, the Netherlands; Institute for Cardiovascular Prevention, Ludwig Maximilian University of Munich, Munich, Germany (C.W., E.L., O.S.); and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. (DZHK) (German Centre for Cardiovascular Research), partner site of Munich Heart Alliance, Munich, Germany (C.W., O.S.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Silvestre-Roig
authors.forename: Menno P
authors.initials: MP
authors.lastname: de Winther
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Mat J
authors.initials: MJ
authors.lastname: Daemen
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E
keywords: atherosclerosis; efferocytosis; macrophages; necrotic core; neutrophils