Proresolving Lipid Mediators Restore Balance to the Vulnerable Plaque
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Atherosclerosis, the precursor to acute coronary syndromes, is a disease of chronic inflammation triggered initially by the focal subendothelial retention of apolipoprotein B100–containing lipoproteins and exacerbated by other risk factors, such as smoking, diabetes mellitus, and hypertension.1,2 The persistence of these stimuli promotes a cycle of nonresolving inflammation that promotes atherosclerotic lesion development and, most importantly, progression to the unique types of necrotic plaques that cause ACS. In order for inflammation to resolve, there must not only be an abatement of initiating risk factors but also an initiation of proresolving molecular and cellular pathways that act to restore tissue homeostasis and promote repair. On the basis of the observations of human and animal atherosclerotic plaque features, genetic and therapy-based causation studies in mice, and cell culture studies with macrophages, researchers over the past two decades have proposed that defective resolution drives atherosclerosis progression. For example, advanced atherosclerosis is characterized by failure to reduce plaque inflammatory cell number, inefficiency in removing dying cells, and suboptimal tissue repair. However, the molecular basis of defective inflammation in atherosclerosis remained to be precisely defined.
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The inflammation resolution program is carried out by several molecular and cellular effectors. Among these are a superfamily of unsaturated fatty acid–derived lipid mediators referred to as specialized proresolving mediators or SPMs. SPMs are biosynthesized by inflammatory cells during self-limited inflammation and, by interacting with specific cell-surface receptors on immune cells and other cell types, trigger processes that dampen inflammation and promote tissue repair. Moreover, exogenously administered SPMs and other proresolving mediators have shown efficacy in triggering resolution of several types of chronic diseases, including atherosclerosis. Although characterized within human arterial cells in the early 1990s by Brezinski et al,3 a comprehensive and direct cataloging of SPMs within atherosclerotic lesions is only …