A critical goal in heart research is to elucidate the mechanisms that promote clinically significant atherosclerosis and then use this knowledge to design novel therapies. The overarching concept that a form the basis of this proposal is that plaque progression represents a pathologic process called defective inflammation resolution. The proposal is based on strong in vitro and in vivo data supporting a critical role for the macrophage (Mf) MerTK receptor in the resolution response--a response that goes awry in advanced atherosclerosis. MerTK enables Mfs to carry out efferocytosis, a critical resolving process in atherosclerosis, and to promote the synthesis of specialized pro-resolving mediators (SPMs), including lipoxin A4 (LXA4) and resolvin D1 (RvD1). Moreover, in inflammatory settings including in advanced atherosclerotic lesions, MerTK is destroyed by ADAM17-mediated cleavage. We propose that this process compromises both efferocytosis and the synthesis of SPMs, leading to the progression of the type of necrotic, inflammatory plaques that, in humans, are clinically dangerous. In this proposal, Aim 1 will further explore the hypothesis that MerTK signals an inflammation resolution response in Mfs, and that MerTK cleavage in atherosclerosis compromises resolution and promotes plaque progression. We will investigate the mechanisms linking MerTK signaling to SPM synthesis and then test the importance of MerTK cleavage in defective efferocytosis, defective mediator synthesis, and plaque progression in atherosclerosis by comparing WD-fed MertkWT Ldlr-/- mice with MertkCR Ldlr-/- mice, which is a unique model in which endogenous Mertk has been replaced by a fully functional cleavage-resistance Mertk.
Aim 2 will explore the regulation of MerTK cleavage by athero-relevant factors and SPMs, both in vitro and in atherosclerosis. We will address several hypotheses as to how athero-relevant factors promote ADAM17-mediated MerTK cleavage and, based on new data, how SPMs suppress MerTK cleavage. At the conclusion of this project, we hope to have elucidated new mechanistic links between inflammation resolution and atherosclerosis, which could provide the basis for new drugs that block plaque progress in high-risk humans. Atherothrombotic vascular disease is the leading cause of death in the industrialized world, with global spread predicted for the future. Important mechanistic and therapeutic gaps exist in combatting this disease. This proposal will study mechanisms that promote atherosclerosis progression in a manner that has the potential to be highly translatable to human therapy through the use of pro-resolving therapy.
Heart disease is the leading cause of morbidity and mortality in developed nations with an enormous societal and economic burden, and dangerous atherosclerosis plaques can develop due to a maladaptive chronic inflammatory response, which ultimately leads to blood clot formation and death in the form of heart attacks. In view of the fact that only certain types of atherosclerotic lesions reach this advanced stage of clinical relevance, the overall objective of this proposal is to understand the processes that influence the formation of these dangerous atherosclerotic lesions-and to do so in a manner that has future therapeutic potential. In this context, we will study the mechanisms of a fundamental protective process that goes awry in atherosclerosis-called inflammation resolution. The proposal is based on the discovery of a new process that causes defective inflammation resolution in atherosclerosis and how therapy directed at this process can prevent the progression of atherosclerosis.
|Cai, Bishuang; Kasikara, Canan; Doran, Amanda C et al. (2018) MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci Signal 11:|
|Proto, Jonathan D; Doran, Amanda C; Gusarova, Galina et al. (2018) Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution. Immunity 49:666-677.e6|
|Proto, Jonathan D; Doran, Amanda C; Subramanian, Manikandan et al. (2018) Hypercholesterolemia induces T cell expansion in humanized immune mice. J Clin Invest 128:2370-2375|
|Kasikara, Canan; Doran, Amanda C; Cai, Bishuang et al. (2018) The role of non-resolving inflammation in atherosclerosis. J Clin Invest 128:2713-2723|
|Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568|
|Yurdagul Jr, Arif; Doran, Amanda C; Cai, Bishuang et al. (2017) Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis. Front Cardiovasc Med 4:86|
|Tabas, Ira (2017) 2016 Russell Ross Memorial Lecture in Vascular Biology: Molecular-Cellular Mechanisms in the Progression of Atherosclerosis. Arterioscler Thromb Vasc Biol 37:183-189|
|Wang, Ying; Subramanian, Manikandan; Yurdagul Jr, Arif et al. (2017) Mitochondrial Fission Promotes the Continued Clearance of Apoptotic Cells by Macrophages. Cell 171:331-345.e22|
|DeBerge, Matthew; Yeap, Xin Yi; Dehn, Shirley et al. (2017) MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res 121:930-940|
|Wang, Ying; Wang, Wei; Wang, Nan et al. (2017) Mitochondrial Oxidative Stress Promotes Atherosclerosis and Neutrophil Extracellular Traps in Aged Mice. Arterioscler Thromb Vasc Biol 37:e99-e107|
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