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comparing WD-fed MertkWT Ldlr-/- mice with MertkCR Ldlr-/- mice, which is a unique model in which endogenous Mertk has been replaced by a fully functional cleavage-resistance Mertk.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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL132412-01
Application #
9120607
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Hasan, Ahmed AK
Project Start
2016-03-15
Project End
2020-02-29
Budget Start
2016-03-15
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$508,137
Indirect Cost
$172,805
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Fredman, Gabrielle; Tabas, Ira (2017) Boosting Inflammation Resolution in Atherosclerosis: The Next Frontier for Therapy. Am J Pathol 187:1211-1221
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
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
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
Ouimet, Mireille; Ediriweera, Hasini; Afonso, Milessa Silva et al. (2017) microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis. Arterioscler Thromb Vasc Biol 37:1058-1067
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
Tabas, Ira; Lichtman, Andrew H (2017) Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 47:621-634
Doran, Amanda C; Ozcan, Lale; Cai, Bishuang et al. (2017) CAMKII? suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest 127:4075-4089
Subramanian, Manikandan; Proto, Jonathan D; Matsushima, Glenn K et al. (2016) Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression. Sci Rep 6:39111

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