REVIEW Necrotic cell death in atherosclerosis Wim Martinet • Dorien M. Schrijvers • Guido R. Y. De Meyer Received: 18 March 2011 / Revised: 10 May 2011 / Accepted: 11 May 2011 / Published online: 25 May 2011 Ó Springer-Verlag 2011 Abstract Necrosis is a type of cell death characterized by a gain in cell volume, swelling of organelles, rupture of the plasma membrane and subsequent loss of intracellular con- tents. For a long time, the process has been considered as a merely accidental and uncontrolled form of cell death, but accumulating evidence suggests that it can also occur in a regulated fashion. Morphological studies using transmission electron microscopy indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Various stimuli in the plaque including high levels of oxidative stress, depletion of cellular ATP, impaired clearance of apoptotic cells and increased intracellular calcium may cause necrotic death. Although the role of necrosis in ath- erosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis through induction of inflammation and enlargement of the necrotic core. In addition, necrosis contributes to plaque instability by releasing tissue factor, matrix degrading proteases and pro- angiogenic compounds. Therapeutic agents against necrosis are limited, but efforts have recently been made to inhibit the necrotic pathway or its pro-inflammatory effects. Keywords Cell death Á Necrosis Á Apoptosis Á Necrotic core Á Atherosclerosis Introduction Atherosclerosis is a disease of large- and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall [19, 49]. This buildup results in atherosclerotic plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow, and diminished oxygen supply to target organs. Despite tremendous advances in identifying [43, 95] and treating vulnerable atherosclerotic plaques [25, 27, 58, 76, 91], the incidence of death and disability caused by such lesions still remains the number one health threat in developed countries. In the last 15 years, numerous studies underscored the relevance and importance of cell death, in particular apoptosis, to plaque progression and stability [42, 81, 84, 94]. Indeed, apoptosis is a major event in atherosclerosis, with increasing frequencies (up to 1–2%) as the plaque develops. In contrast to apoptosis, necrotic cell death has been a poorly investigated phenomenon in atherosclerosis, given the apparent lack of any review article on this subject. One of the reasons is that reliable methods for detection of necrosis in situ are not available. C9 immunostaining has previously been used to detect myocardial necrosis [18], but the reliability and broad applicability of this approach is unclear. As a consequence, the occurrence of necrosis in in vivo models is mostly defined morphologically. Because necrosis may be an important cell death mode that is pathologically relevant, the aim of the present review is to provide a comprehensive overview of our current knowledge of necrosis in atherosclerosis. Definition of necrosis Cells undergoing necrosis are characterized by cytoplasmic swelling, irreversible plasma membrane damage and the W. Martinet (&) Á D. M. Schrijvers Á G. R. Y. De Meyer Division of Pharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium e-mail: wim.martinet@ua.ac.be 123 Basic Res Cardiol (2011) 106:749–760 DOI 10.1007/s00395-011-0192-x