Ira Tabas

Columbia University, New York, New York, United States

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Publications (163)1550.45 Total impact

  • Circulation Research 11/2015; 117(11):909-913. DOI:10.1161/CIRCRESAHA.115.307609 · 11.02 Impact Factor
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    ABSTRACT: Obesity-induced inflammation in visceral adipose tissue (VAT) is a major contributor to insulin resistance and type 2 diabetes. Whereas innate immune cells, notably macrophages, contribute to visceral adipose tissue (VAT) inflammation and insulin resistance, the role of adaptive immunity is less well defined. To address this critical gap, we used a model in which endogenous activation of T cells was suppressed in obese mice by blocking MyD88-mediated maturation of CD11c+ antigen-presenting cells. VAT CD11c+ cells from Cd11cCre+Myd88fl/fl vs. control Myd88fl/fl mice were defective in activating T cells in vitro, and VAT T and B cell activation was markedly reduced in Cd11cCre+Myd88fl/fl obese mice. However, neither macrophage-mediated VAT inflammation nor systemic inflammation were altered in Cd11cCre+Myd88fl/fl mice, thereby enabling a focused analysis on adaptive immunity. Unexpectedly, fasting blood glucose, plasma insulin, and the glucose response to glucose and insulin were completely unaltered in Cd11cCre+Myd88fl/fl vs. control obese mice. Thus, CD11c+ cells activate VAT T and B cells in obese mice, but suppression of this process does not have a discernible effect on macrophage-mediated VAT inflammation or systemic glucose homeostasis.
    PLoS ONE 08/2015; 10(8):e0135842. DOI:10.1371/journal.pone.0135842 · 3.23 Impact Factor
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    G K Hansson · P Libby · I Tabas ·
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    ABSTRACT: Atherosclerosis is a maladaptive, nonresolving chronic inflammatory disease that occurs at sites of blood flow disturbance. The disease usually remains silent until a breakdown of integrity at the arterial surface triggers the formation of a thrombus. By occluding the lumen, the thrombus or emboli detaching from it elicits ischaemic symptoms that may be life-threatening. Two types of surface damage can cause atherothrombosis: plaque rupture and endothelial erosion. Plaque rupture is thought to be caused by loss of mechanical stability, often due to reduced tensile strength of the collagen cap surrounding the plaque. Therefore, plaques with reduced collagen content are thought to be more vulnerable than those with a thick collagen cap. Endothelial erosion, on the other hand, may occur after injurious insults to the endothelium instigated by metabolic disturbance or immune insults. This review discusses the molecular mechanisms involved in plaque vulnerability and the development of atherothrombosis. © 2015 The Association for the Publication of the Journal of Internal Medicine.
    Journal of Internal Medicine 08/2015; 278(5). DOI:10.1111/joim.12406 · 6.06 Impact Factor
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    ABSTRACT: The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38α mitogen-activated protein kinase, and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 06/2015; DOI:10.2337/db14-1945 · 8.10 Impact Factor
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    ABSTRACT: Myeloid-derived C/EBP-homologous protein (CHOP), an effector of the endoplasmic reticulum (ER) stress-induced Unfolded Protein Response, promotes macrophage apoptosis in advanced atherosclerosis, but the role of CHOP in vascular smooth muscle cells (VSMCs) in atherosclerosis is not known. To investigate the role of CHOP in SM22α(+) VSMCs in atherosclerosis. Chop(fl/fl) mice were generated and crossed into the Apoe(-/-) and SM22α-CreKI(+) backgrounds. SM22α-CreKI causes deletion of floxed genes in adult SMCs. After 12 wks of Western-type diet feeding, the content of α-actin-positive cells in aortic root lesions was decreased in Chop(fl/fl)SM22α-CreKI(+)Apoe(-/-) vs. control Chop(fl/fl)Apoe(-/-) mice, and aortic explant-derived VSMCs from the VSMC-CHOP-deficient mice displayed reduced proliferation. Krüppel-like factor 4 (KLF4), a key suppressor of VSMC proliferation, was increased in lesions and aortic VSMCs from Chop(fl/fl)SM22α-CreKI(+)Apoe(-/-) mice, and silencing Klf4 in CHOP-deficient VSMCs restored proliferation. CHOP deficiency in aortic VSMCs increased KLF4 through two mechanisms mediated by the ER stress effector ATF4: transcriptional induction of Klf4 mRNA and decreased proteasomal degradation of KLF4 protein. These findings in SM22α-CHOP-deficient mice imply that CHOP expression in SM22α(+) VSMCs promotes cell proliferation by down-regulating KLF4. The mechanisms involve newly discovered roles of CHOP in the transcriptional and post-translational regulation of KLF4.
    Circulation Research 04/2015; 116(11). DOI:10.1161/CIRCRESAHA.116.305602 · 11.02 Impact Factor
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    ABSTRACT: Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how in-depth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy. © 2015 Tabas et al.
    The Journal of Cell Biology 04/2015; 209(1):13-22. DOI:10.1083/jcb.201412052 · 9.83 Impact Factor
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    ABSTRACT: Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2-26 (Ac2-26). Collagen IV (Col IV)-targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr(-/-) mice. When administered to mice with preexisting lesions, Col IV-Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 02/2015; 7(275):275ra20-275ra20. DOI:10.1126/scitranslmed.aaa1065 · 15.84 Impact Factor
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    Alan Daugherty · Ira Tabas · Daniel J Rader ·

    Arteriosclerosis Thrombosis and Vascular Biology 01/2015; 35(1):11-2. DOI:10.1161/ATVBAHA.114.304833 · 6.00 Impact Factor
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    ABSTRACT: Rationale: Granulocyte macrophage colony-stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression, the process that gives rise to clinically dangerous plaques, is unknown. Objective: To understand the role of GM-CSF in advanced atherosclerotic plaque progression. Methods and results: Ldlr(-/-) mice and Csf2(-/-)Ldlr(-/-) mice were fed a Western-type diet for 12 weeks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF-deficient mice showed a substantial decrease in 2 key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF-mediated production of interleukin-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein Bcl-2 (B-cell lymphoma 2) and by increasing oxidative stress. Conclusions: In low-density lipoprotein-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its interleukin-23-inducing activity rather than its role as a growth factor.
    Circulation Research 10/2014; 116(2). DOI:10.1161/CIRCRESAHA.116.304794 · 11.02 Impact Factor
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    ABSTRACT: Protein therapeutics have gained attention recently for treatment of a myriad of human diseases due to their high potency and unique mechanisms of action. We present the development of a novel polymeric thermosponge nanoparticle for efficient delivery of labile proteins using a solvent-free polymer thermo-expansion mechanism with clinical potential, capable of effectively delivering a range of therapeutic proteins in a sustained manner with no loss of bioactivity, with improved biological half-lives and efficacy in vivo.
    Nano Letters 10/2014; 14(11). DOI:10.1021/nl502994y · 13.59 Impact Factor
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    ABSTRACT: Imbalances between proinflammatory and proresolving mediators can lead to chronic inflammatory diseases. The balance of arachidonic acid-derived mediators in leukocytes is thought to be achieved through intracellular localization of 5-lipoxygenase (5-LOX): nuclear 5-LOX favors the biosynthesis of proinflammatory leukotriene B4 (LTB4), whereas, in theory, cytoplasmic 5-LOX could favor the biosynthesis of proresolving lipoxin A4 (LXA4). This balance is shifted in favor of LXA4 by resolvin D1 (RvD1), a specialized proresolving mediator derived from docosahexaenoic acid, but the mechanism is not known. Here we report a new pathway through which RvD1 promotes nuclear exclusion of 5-LOX and thereby suppresses LTB4 and enhances LXA4 in macrophages. RvD1, by activating its receptor formyl peptide receptor2/lipoxin A4 receptor, suppresses cytosolic calcium and decreases activation of the calcium-sensitive kinase calcium-calmodulin-dependent protein kinase II (CaMKII). CaMKII inhibition suppresses activation P38 and mitogen-activated protein kinase-activated protein kinase 2 kinases, which reduces Ser271 phosphorylation of 5-LOX and shifts 5-LOX from the nucleus to the cytoplasm. As such, RvD1's ability to decrease nuclear 5-LOX and the LTB4:LXA4 ratio in vitro and in vivo was mimicked by macrophages lacking CaMKII or expressing S271A-5-LOX. These findings provide mechanistic insight into how a specialized proresolving mediator from the docosahexaenoic acid pathway shifts the balance toward resolution in the arachidonic acid pathway. Knowledge of this mechanism may provide new strategies for promoting inflammation resolution in chronic inflammatory diseases.
    Proceedings of the National Academy of Sciences 09/2014; 111(40). DOI:10.1073/pnas.1410851111 · 9.67 Impact Factor
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    Lale Ozcan · Ira Tabas ·

    Aging 06/2014; 6(6). · 4.70 Impact Factor
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    ABSTRACT: Inflammation contributes to many of the characteristics of plaques implicated in the pathogenesis of acute coronary syndromes. Moreover, inflammatory pathways not only regulate the properties of plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis. This synthesis will provide an update on the fundamental mechanisms of inflammatory responses that govern acute coronary syndromes and also highlight the ongoing balance between proinflammatory mechanisms and endogenous pathways that can promote the resolution of inflammation. An appreciation of the countervailing mechanisms that modulate inflammation in relation to acute coronary syndromes enriches our fundamental understanding of the pathophysiology of this important manifestation of atherosclerosis. In addition, these insights provide glimpses into potential novel therapeutic interventions to forestall this ultimate complication of the disease.
    Circulation Research 06/2014; 114(12):1867-79. DOI:10.1161/CIRCRESAHA.114.302699 · 11.02 Impact Factor
  • Gabrielle Fredman · Lale Ozcan · Ira Tabas ·
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    ABSTRACT: The interactions between cardiovascular disease (CVD) and insulin resistance syndromes suggest the possibility of joint targets for cardiometabolic research. The best drugs would go beyond minimizing adverse effects and have protective actions against both metabolic disease and CVD. In this perspective, we will outline a few examples in which a deep mechanistic understanding of the many cellular pathways that contribute to type 2 diabetes and CVD, regardless of cell type, have resulted in common upstream pathogenic pathways that can be therapeutically targeted.
    Science translational medicine 06/2014; 6(239):239ps5. DOI:10.1126/scitranslmed.3008908 · 15.84 Impact Factor
  • Ira Tabas · Ying Wang ·
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    ABSTRACT: Mitochondrial-derived reactive oxygen species (mtROS) is one of the major sources of cellular ROS, and excessive mtROS is associated with atherosclerosis progression in both human and mouse models. This review aims to summarize the most recent studies showing the existence, the causes and pathological consequences of excessive mtROS in atherosclerosis. Despite numerous association and causation studies demonstrating the importance of mtROS in atherosclerosis progression, the failure of antioxidant therapy in human randomized clinical trials demands more definitive, cell-type specific investigations. Better mechanistic understanding of mtROS in atherosclerosis may lead to more effective therapeutic strategies.
    Journal of atherosclerosis and thrombosis 04/2014; 21(5). DOI:10.5551/jat.23929 · 2.73 Impact Factor
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    ABSTRACT: Coronary heart disease is associated with monocytosis. Studies using animal models of monocytosis and atherosclerosis such as ApoE(-/-) mice have shown bone marrow (BM) hematopoietic stem and multipotential progenitor cell (HSPC) expansion, associated with increased cell surface expression of the common β subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor (CBS) on HSPCs. ApoE(-/-) mice also display increased granulocyte macrophage colony-stimulating factor-dependent monocyte production in the spleen. We investigated the role of the CBS in cholesterol-driven HSPC expansion, monocytosis, and atherosclerosis. (-/-) mice were transplanted with ApoE(-/-)Cbs(-/-) or ApoE(-/-) BM followed by Western-type diet feeding. Compared with ApoE(-/-) BM-transplanted controls, ApoE(-/-)Cbs(-/-) BM-transplanted mice had reduced BM and splenic HSPC proliferation, fewer blood monocytes and neutrophils, and reduced macrophage content and area of early atherosclerotic lesions. More advanced lesions showed diminished macrophage and collagen content; however, lesion size was unchanged, reflecting an increase in necrotic core area, associated with a marked decrease in Abcg1 expression and increased macrophage apoptosis. Compared with wild-type mice, Western-type diet-fed ApoE(-/-) mice showed increased CBS expression on granulocyte macrophage colony-stimulating factor-producing innate response activator B cells and expansion of this population. ApoE(-/-)Cbs(-/-) BM-transplanted Ldlr(-/-) mice showed a marked decrease in innate response activator B cells compared with ApoE(-/-) BM-transplanted Ldlr(-/-) controls. Increased levels of CBS on HSPCs and splenic innate response activator B cells lead to expansion of these populations in ApoE(-/-) BM-transplanted Ldlr(-/-) mice, contributing to monocytosis and increased lesional macrophage content. However, in more advanced lesions, the CBS also has a role in atherosclerotic plaque stabilization.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2014; 34(5). DOI:10.1161/ATVBAHA.113.303097 · 6.00 Impact Factor
  • Manikandan Subramanian · Ira Tabas ·

    Nature Immunology 02/2014; 15(3):213-5. DOI:10.1038/ni.2826 · 20.00 Impact Factor
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    ABSTRACT: The phagocytosis of apoptotic cells (ACs), or efferocytosis, by DCs is critical for self-tolerance and host defense. Although many efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex - composed of the receptor tyrosine kinase AXL, LDL receptor-related protein-1 (LRP-1), and RAN-binding protein 9 (RANBP9) - that mediates DC efferocytosis and antigen cross-presentation. We found that AXL bound ACs, but required LRP-1 to trigger internalization, in murine CD8α+ DCs and human-derived DCs. AXL and LRP-1 did not interact directly, but relied on RANBP9, which bound both AXL and LRP-1, to form the complex. In a coculture model of antigen presentation, the AXL/LRP-1/RANBP9 complex was used by DCs to cross-present AC-associated antigens to T cells. Furthermore, in a murine model of herpes simplex virus-1 infection, mice lacking DC-specific LRP-1, AXL, or RANBP9 had increased AC accumulation, defective viral antigen-specific CD8+ T cell activation, enhanced viral load, and decreased survival. The discovery of this multiprotein complex that mediates functionally important DC efferocytosis in vivo may have implications for future studies related to host defense and DC-based vaccines.
    The Journal of clinical investigation 02/2014; 124(3). DOI:10.1172/JCI72051 · 13.22 Impact Factor
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    ABSTRACT: Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell-type specific causation studies in vivo are lacking, and the molecular mechanisms of potential pro-atherogenic effects remain to be determined. To assess the importance of macrophage mitoOS in atherogenesis and explore the underlying molecular mechanisms. We first validated Western-type diet-fed Ldlr(-/-) mice as a model of human mitoOS-atherosclerosis association by showing that a marker of mitoOS in lesional macrophages, non-nuclear oxidative DNA damage, correlates with aortic root lesion development. To investigate the importance of macrophage-mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6c(hi) monocyte infiltration into lesions, and lower levels of the monocyte chemotactic protein-1 (MCP-1). The decrease in lesional MCP-1 was associated with suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the pro-inflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed MCP-1 expression by decreasing activation of the IΚ-kinase-RelA NF-κB pathway. MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-ΚB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis.
    Circulation Research 12/2013; 114(3). DOI:10.1161/CIRCRESAHA.114.302153 · 11.02 Impact Factor
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    ABSTRACT: A hallmark of obesity is selective suppression of hepatic insulin signaling ("insulin resistance"), but critical gaps remain in our understanding of the molecular mechanisms. We now report a major role for hepatic CaMKII, a calcium-responsive kinase that is activated in obesity. Genetic targeting of hepatic CaMKII, its downstream mediator p38, or the p38 substrate and stabilizer MK2 enhances insulin-induced p-Akt in palmitate-treated hepatocytes and obese mouse liver, leading to metabolic improvement. The mechanism of improvement begins with induction of ATF6 and the ATF6 target p58(IPK), a chaperone that suppresses the PERK-p-eIF2α-ATF4 branch of the UPR. The result is a decrease in the ATF4 target TRB3, an inhibitor of insulin-induced p-Akt, leading to enhanced activation of Akt and its downstream metabolic mediators. These findings increase our understanding of the molecular mechanisms linking obesity to selective insulin resistance and suggest new therapeutic targets for type 2 diabetes and metabolic syndrome.
    Cell metabolism 11/2013; 18(6). DOI:10.1016/j.cmet.2013.10.011 · 17.57 Impact Factor

Publication Stats

14k Citations
1,550.45 Total Impact Points


  • 1995-2015
    • Columbia University
      • • Department of Medicine
      • • Department of Pathology & Cell Biology
      • • Department of Physiology and Cellular Biophysics
      • • Division of Molecular Medicine
      • • College of Physicians and Surgeons
      New York, New York, United States
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 1995-2006
    • CUNY Graduate Center
      New York, New York, United States
  • 1998
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
    • Cornell University
      • Department of Medicine
      Итак, New York, United States