Atherosclerotic vascular disease is the leading cause of death in most populations. Only a minority of atherosclerotic lesions actually cause clinical disease, and a key, distinguishing feature of those that do is plaque necrosis. The overall objective of this proposal is to gain in-depth understanding of the signaling pathways involved in plaque necrosis, with the ultimate goal of developing novel therapeutic measures for high-risk individuals. Our and others'previous work has provided evidence that plaque necrosis and inflammation are promoted by leukocyte/macrophage (Mf) apoptosis in advanced lesions, a major cause of which is exposure to endoplasmic reticulum (ER) stress and reactive oxygen/nitrogen species. However, there are critical gaps in our understanding of the mechanisms that trigger these stress pathways and how they lead to apoptosis. Based on new data in the PI's lab, the proposal will address these gaps by focusing on new upstream and downstream signaling pathways involved in Mf apoptosis. We hypothesize that oxidative stress originating from the mitochondria, referred to as "mitoOS," plays a key upstream role and that a novel Bax/Bak-caspase 8 (casp8) pathway plays a major downstream role in advanced lesional Mf apoptosis and plaque necrosis.
In Aim 1, we will elucidate how mitoOS induces the ER- stress apoptosis effector CHOP;evaluate whether mitoOS pathways in addition to CHOP promote Mf apoptosis;and explore the role of 2 inducers of mitoOS, Drp1 and mitochondrial Ca2+ uptake. Most importantly, we will study fat-fed Ldlr-/- mice in which (a) Mfs express mitochondria-targeted catalase, which suppresses mitoOS and apoptosis;and (b) Drp1 is absent in Mfs, which blocks mitochondrial fission, mitoOS, and apoptosis.
In Aim 2, we will explore the mechanism of the new Bax/Bak-casp8 apoptosis pathway and investigate links to the mitoOS-CHOP pathway in Aim 1. We will then test causation in advanced atherosclerosis, following the same overall strategy as in Aim 1, using two unique models: mice whose Mfs lack Bax/Bak and mice expressing a form of casp8 that specifically blocks its role in apoptosis. We will also explore the presence of act-casp8 in advanced human atheromata. These combined studies will add significantly to our knowledge of how clinically dangerous atherosclerotic plaques form and how the process may be therapeutically suppressed. Summary of Relevance: Coronary artery disease is the leading killer in most populations. Current therapies are focused on risk factor reduction. A complementary approach directly targeting lesion progression could be extremely valuable in decreasing heart disease. This proposal is focused on specific processes that are known to promote atherosclerosis progression and which, with knowledge gained herein, could be excellent drug targets.

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-called vulnerable plaques-trigger these events, the overall objective of this proposal is to add to our knowledge of what processes influence the formation of these dangerous atherosclerotic lesions. In this context, we will study a very important process leading to the formation of vulnerable plaques-a process involving the death of a lesional cell type called the macrophage-with the ultimate goal of developing therapeutic strategies 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 #
5R01HL075662-11
Application #
8602521
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Kirby, Ruth
Project Start
2003-12-01
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
11
Fiscal Year
2014
Total Cost
$752,000
Indirect Cost
$282,000
Name
Columbia University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Tabas, Ira (2016) Heart disease: Death-defying plaque cells. Nature 536:32-3
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
Ozcan, Lale; Ghorpade, Devram S; Zheng, Ze et al. (2016) Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep 15:2214-25
Tabas, Ira (2016) 2016 Russell Ross Memorial Lecture in Vascular Biology: Molecular-Cellular Mechanisms in the Progression of Atherosclerosis. Arterioscler Thromb Vasc Biol :
Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859
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Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2016) MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A 113:6526-31
Fredman, Gabrielle; Kamaly, Nazila; Spolitu, Stefano et al. (2015) Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci Transl Med 7:275ra20
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

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