Atherothrombotic vascular disease, the cause of heart attacks, strokes, and sudden death, is the leading cause of death in the industrialized world. These acute vascular events are triggered by disruption of advanced atherosclerotic plaques that have large necrotic areas. Plaque necrosis is caused by macrophage (Mf) death, or """"""""apoptosis,"""""""" in advanced lesions. The PI's laboratory introduced the concept that endoplasmic reticulum (ER) stress in advanced lesional Mfs is an important mechanism of Mf death. ER stress induces a pro-apoptotic effector called CHOP, which conspires with other pro-apoptotic """"""""hits"""""""" to induce Mf death. The overall objective of this proposal is to expand these concepts in three critical areas: (a) discrimination of the roles of ER stress in advanced vs. early lesions and in Mfs vs. endothelial cells;(b) elucidation of the role of increased cytosolic Ca2+, a by-product of ER stress, in the multi-hit model of Mf apoptosis;and (c) assessment of whether decreased advanced lesional Mf apoptosis and plaque necrosis via genetic manipulation of the multi-hit/ER stress pathway has a beneficial effect in plaque disruption.
In Aim I, reciprocal bone marrow transplant (BMT) experiments using Chop-/- and Ldlr-/- mice will test the hypothesis that endothelial CHOP promotes early atherogenesis while Mf CHOP promotes advanced atherosclerosis.
Aim II will address the hypothesis that elevation of cytosolic calcium induced by ER stress amplifies two important pro-apoptotic pathways of the multi-hit model, one involving toll-like receptor 4 and c-Jun-NH(2)-terminal kinase, and the other involving Ca2+-calmodulin kinase II and serine-phosphorylated STAT1. BMT experiments in Aim III will test the hypothesis that Mf-STAT1 deficiency will decrease Mf death and plaque necrosis in advanced atherosclerotic lesions. The proposed link between plaque necrosis and plaque disruption will be addressed in Aim IV by determining whether plaque disruption in Apoe- /- mice with Mf-targeted expression of activated MMP9 is decreased in the setting of CHOP or combined CHOP/STAT1 deficiency. Through these studies, we hope to conceive novel therapeutic strategies to prevent advanced plaque progression and atherothrombotic vascular disease. Indeed, the Mf apoptosis pathway being studied here has been shown to be amplified in the setting of diabetes, which represents the major driving force predicted to increase atherothrombotic vascular disease in the immediate and longer term future.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kirby, Ruth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
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
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
Tabas, Ira; Bornfeldt, Karin E (2016) Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res 118:653-67
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 15:2214-2225
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
Tabas, Ira (2016) Heart disease: Death-defying plaque cells. Nature 536:32-3

Showing the most recent 10 out of 93 publications