A key event in atherothrombotic vascular disease is the conversion of subclinical lesions to disrupted plaques that trigger acute lumenal thrombosis. The PI's laboratory is focused on cellular and molecular processes involved in a critical feature of dangerous plaques, the necrotic core, which contributes to inflammation, plaque disruption, and thrombosis. Necrotic cores arise from the apoptosis of advanced lesional macrophages coupled with defective phagocytic clearance, or "efferocytosis," of the apoptotic macrophages. The objective of this proposal is to elucidate mechanisms and consequences of defective efferocytosis in the two major populations of monocyte-derived cells in advanced atherosclerosis, macrophages and dendritic-like cells (DCs).
Aim 1 will explore the hypothesis that ADAM17-mediated cleavage of the efferocytosis receptor MerTK in advanced lesional macrophages contributes to defective efferocytosis and plaque necrosis.
Sub aim 1 A will explore in vitro and in vivo a new mechanism that leads to MerTK cleavage involving athero-relevant activators of a CD36/Toll-like receptor 2/NADPH oxidase/PKC4 pathway. One such activator is apolipoprotein(a), which associates with apoB to form lipoprotein(a) [Lp(a)] and is genetically associated with human CAD.
Sub aim 1 B will first investigate the temporal and quantitative relationships between lesional sol-Mer and plaque stage in murine and human atheromata and then will test causation by using a mouse with non-cleavable MerTK, which we predict will be protected from defective efferocytosis and plaque necrosis during lesion progression.
Aim 2 will explore the hypothesis that enrichment of atheromata with mature DCs (mDCs), which lose efferocytic capacity, contributes to defective efferocytosis and plaque necrosis. We have shown that areas of advanced plaques enriched in mDCs, like those enriched in macrophages, are located near areas of plaque necrosis and have even worse efferocytosis than macrophage-rich regions.
Sub aim 2 A will test the hypothesis that MerTK cleavage in DCs leads to defective efferocytosis by promoting DC maturation through inflammatory signaling.
Sub aim 2 B will first study the relationships among lesional DCs, efferocytosis, and plaque necrosis in human carotid atheromata and in plaques of fat-fed Ldlr-/- and Apoe-/- mice and will then test causation by assessing the effect of two genetic manipulations that suppress DC development or maturation-GM-CSF deficiency and DC MyD88 deficiency. Achieving the stated objective will provide critical information for understanding how necrotic cores form and may help in the design of new therapeutic strategies to prevent the clinical progression of atherosclerotic lesions.

Public Health Relevance

Heart attacks, strokes, and sudden death due to heart disease-the leading cause of death in our society-are triggered by a sudden cutting off of the blood supply feeding these organs by platelet plugs, which form because the vessel in that area has a disease process called "atherosclerosis" ("hardening of the arteries"). In view of the fact that only certain types of atherosclerotic lesions trigger platelet plugs, the overall objective of this proposal is to understand what processes influence the formation of these dangerous atherosclerotic lesions. In this context, we will study a fundamental protective process carried out by certain types of white blood cells, called "efferocytosis," which becomes defective in lesions destined to become dangerous and thus may offer new clues to prevent dangerous atherosclerotic lesions from forming.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL107497-01A1
Application #
8233659
Study Section
Special Emphasis Panel (ZRG1-VH-H (02))
Program Officer
Hasan, Ahmed AK
Project Start
2011-12-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$400,000
Indirect Cost
$150,000
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
Subramanian, Manikandan; Thorp, Edward; Tabas, Ira (2015) Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling. Circ Res 116:e13-24
Wang, Mi; Subramanian, Manikandan; Abramowicz, Sandra et al. (2014) Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency. Arterioscler Thromb Vasc Biol 34:976-84
Subramanian, Manikandan; Tabas, Ira (2014) Dendritic cells in atherosclerosis. Semin Immunopathol 36:93-102
Wang, Ying; Tabas, Ira (2014) Emerging roles of mitochondria ROS in atherosclerotic lesions: causation or association? J Atheroscler Thromb 21:381-90
Subramanian, Manikandan; Tabas, Ira (2014) A new RIDDle in DC-mediated cross-presentation. Nat Immunol 15:213-5
Fredman, Gabrielle; Ozcan, Lale; Tabas, Ira (2014) Common therapeutic targets in cardiometabolic disease. Sci Transl Med 6:239ps5
Subramanian, Manikandan; Hayes, Crystal D; Thome, Joseph J et al. (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J Clin Invest 124:1296-308
Fredman, Gabrielle; Ozcan, Lale; Spolitu, Stefano et al. (2014) Resolvin D1 limits 5-lipoxygenase nuclear localization and leukotriene B4 synthesis by inhibiting a calcium-activated kinase pathway. Proc Natl Acad Sci U S A 111:14530-5
Libby, Peter; Tabas, Ira; Fredman, Gabrielle et al. (2014) Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867-79
Tabas, Ira; Glass, Christopher K (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339:166-72

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