F A C U L T Y   P R O F I L E 

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TABAS, IRA, M.D., Ph.D.
Richard J. Stock Professor, Professor of Physiology & Cellular Biophysics, Medicine and Anatomy and CellBiology, Vice-Chairman of Research

The cellular and molecular biology of macrophages during atherogenesis.

Office: Presbyterian Hospital | 8th floor-east | Room 101B
Telephone: 212.305.9430
Fax: 212.305.4834
Email:
iat1@columbia.edu

Tabas Lab

Current Research

The Tabas laboratory studies the cellular biology of advanced atherosclerotic plaque progression and the cellular-molecular mechanisms linking insulin resistance to enhanced atherosclerosis. The studies on advanced plaque progression have been driven by the findings in humans that <5% of coronary lesions cause acute atherothrombotic vascular disease and that these "vulnerable plaques" are distinguished by the presence of large areas of necrosis that promote inflammation and plaque instability.

The studies on plaque necrosis have focused on two processes that are critical to the generation of advanced lesional necrosis, namely, macrophage (MΦ) apoptosis coupled with defective clearance of the dead cells (efferocytosis"). The apoptosis studies have explored the mechanisms, consequences, and in-vivo relevance of the Integrated Stress Response (ISR), notably the PERK-CHOP branch of the endoplasmic reticulum (ER) stress pathway known as the stress Unfolded Protein Response (UPR); and a non-ER stress pathway involving a kinase called PKR. The laboratory has established a critical link between the UPR and a calcium-induced apoptosis pathway. This pathway involves an ER calcium-release channel called IP3R (inositol-3-phosphate receptor), a calcium-sensitive protein kinase called CaMKII (calcium-calmodulin-dependent protein kinase II), and oxidative stress-generating enzyme, NADPH oxidase. Ongoing work is focused on additional pro-apoptotic processes involving mitochondrial oxidative stress, mitochondrial-calcium interaction, and the death receptor-caspase 8 pathway. Additional new studies are exploring processes that are atheroprotective through preventing advanced lesional MΦ death, defective efferocytosis, and/or inflammation. These processes include autophagy; dendritic cell-mediated regulatory T cell activation; and arachidonic acid-derived lipid mediators that promote inflammation resolution. Efferocytosis studies in the lab are investigating the role and regulation of the MΦ efferocytosis receptor MerTK and the mechanisms and consequences of efferocytosis by plaque dendritic cells.

Obesity, insulin resistance, and type 2 diabetes are becoming the major drivers of atherothrombotic vascular disease worldwide. The Tabas laboratory is part of a collaborative group, funded by an NIH Program Project (PPG) and including the laboratories of Drs. Alan Tall and Domenico (Mimmo) Accili, exploring the cellular and molecular mechanisms of this association. Recent published work from the PPG elucidated mechanisms of enhanced advanced lesional MΦ death and plaque necrosis in the setting of MΦ insulin resistance, and new work in this area has directly linked these findings to calcium-induced apoptosis (above). The PPG has also discovered new pathways in the liver that increase the risk for atherosclerosis, including dyslipidemia, insulin resistance, and hyperglycemia. In this context, the Tabas laboratory has recently discovered that a calcium-IP3R-CaMKII pathway in hepatocytes, similar to the one described above in MΦs, plays a key role in glucagon-mediated excessive glucose production, insulin resistance, fatty liver, and dyslipidemia in the setting of obesity and type 2 diabetes. Ongoing studies are investigating the detailed molecular mechanisms involved in this new pathway.

The ultimate goal of each of these projects is to continually pinpoint areas of therapeutic potential. The lab is particularly interested in new therapies that prevent the conversion of benign atherosclerotic lesions into disease-causing vulnerable plaques—work that is now being carried out using nanoparticles to deliver relevant compounds to atherosclerotic lesions (funded as part of an NIH Program of Excellence in Nanotechnology). The laboratory is also interested in using drugs to disrupt the aforementioned new glucagon-mediated pathway in liver, i.e., to block the generation of systemic, liver-derived atherosclerotic risk factors in the setting of obesity and type 2 diabetes.


Selected Publications

Subramanian, M., Thorp, E., Hansson, G.K., and Tabas, I. (2013) Treg-mediated suppression of atherosclerosis requires MYD88 signaling in dendritic cells. J. Clin. Invest. 123:179-88. PMC3533292

Kamaly, N., Fredman, G., Subramanian, M., Gadde, S., Pesic, A., Cheung, L., Langer, R., Tabas, I., and Farokhzad, O. (2013) Development and in vivo efficacy of targeted polymeric inflammation-resolving nanoparticles. Proc. Natl. Acad. Sci. U.S.A. 110:6506-6511. PMC3631648

Ozcan, L., Backs, J., Olson, E.N., and Tabas, I. (2013) Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metabolism 18:803-815.

Subramanian, M., Hayes, C.D., Thorp, E., Matsushima, G.K., Herz, J., Liu, K., Lakshmana, M., and Tabas, I. (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J. Clin. Invest. 124:1296-1308.

Wang, Y., Wang, G.Z., Rabinovitch,P.S., and Tabas, I. (2013) Macrophage mitochondrial oxidative stress promotes atherosclerosis and NF-B-mediated inflammation in macrophages. Circulation Res. 114:421-433. Selected by Faculty 1000-Prime.

Fredman, G. and Tabas, I. 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. in press/online.

Fredman, G., Kamaly, N., Spolitu, S., Kuriakose, G., Milton, J., Perritti, M., Farokhzad, O., and Tabas I. (2014) Targeted nanoparticles containing the pro-resolving peptide Ac2-26 protect against advanced atherosclerosis. In final revision for Science Transl. Med.

Feng, B, Yao, P.M., Li, Y., Devlin, C., Zhang, D., Harding, H., Sweeney, M., Rong, J.X., Kuriakose, G., Fisher, E.A., Marks, A.R., Ron, D., Tabas, I. (2003) The endoplasmic reticulum as the site of cholesterol-induced cytotoxicity in macrophages. Nature Cell Biology 5:781-792.

Seimon, T.A., Obstfeld, A., Moore, K.J., Golenbock, D.T., and Tabas, I. (2006) Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc. Natl. Acad. Sci. U.S.A. 103:19794-19799.

Thorp, E., Li, G., Seimon, T.A., Kuriakose, G., Ron, D., Tabas, I. (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metabolism 9:474-481. PMCID: PMC2695925

Timmins, J., Ozcan, L., Seimon, T.A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E.N., Anderson, M.E., and Tabas, I. (2009) Calcium/calmodulin-dependent protein kinase II links endo-plasmic reticulum stress with Fas and mitochondrial apoptosis pathways. J. Clin. Invest. 119:2925-2941. PMCID: PMC2752072

Woo, C.W., Cui, D., Arrelano, J., Dorweiler,B., Harding, H., Fitzgerald, K.A., Ron, D., and Tabas, I. (2009) Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signaling. Nature Cell Biol. 11:1473-1480. PMCID: PMC2787632

Seimon, T.A., Liao, X., Magallon, J, Nguyen, M., Witztum, J.L., Tsimikas, S., Moore, K.J., Golenbock, D., and Tabas, I. (2010) Atherosclerosis-relevant CD36 ligands trigger Toll-like receptor 2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metabolism 12:467-482. PMCID: PMC2991104

Moore, K.J. and Tabas, I. (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341-355. PMCID: PMC3111065

Bornfeldt, K. and Tabas, I. (2011) Mechanisms of atherosclerosis in insulin resistance. Cell Metabolism. 14:575-585. PMCID: PMC3217209

Woo, C.W., Kutzler, L., Kimball, S.R., and I. Tabas (2012) Toll-like receptor activation suppresses endoplasmic reticulum stress-induced CHOP through activation of eIF2B. Nature Cell Biol. 14:192-200. PMC3271190

Liao, X., Sluimer, J.C., Wang, Y., Subramanian, M., Brown, K., Pattison, J.S., Robbins, J., Martinez, J., and Tabas, I. (2012) Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metabolism 15:545-553. PMC3322248

Wang, Y., Li, G.., Goode, J., Paz, J.C., Screaton, R., Fischer, W.H., Tabas, I., and Montminy, M. (2012) Inositol 1,4,5-trisphosphate receptor regulates fasting hepatic gluconeogenesis. Nature 485:128-132. PMC3343222

Ozcan, L., Li, G., Accili, D., Tabas I. (2012) Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metabolism 15:739–751. PMC3348356

Subramanian, M., Thorp, E., Hansson, G.K., and Tabas, I. (2013) Treg-mediated suppression of atherosclerosis requires MYD88 signaling in dendritic cells. J. Clin. Invest. 123:179-88. PMC3533292

Tabas, I. and Glass, C.K. (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339:166-172. PMC3608517

Ozcan, L., Backs, J., Olson, E.N., and Tabas, I. (2013) Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling. Cell Metabolism in press

Woo, C.W., Cui, D., Arrelano, J., Dorweiler,B., Harding, H., Fitzgerald, K.A., Ron, D., and Tabas, I. (2009) Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signaling.  In revision for Nature Cell Biol.

Devlin, C., Pipalia, N.H., Liao, X., Schuchman, E.H., Maxfield, F.R., Tabas, I. 2009. Marked improvement in lipid and protein trafficking in a lysosomal storage disease cell by correction of a secondary enzymatic defect.  In revision for Traffic.

Li, S., Sun, Y., Thorp, E., Jehle, A., Viswanathan, S., Kanter, J., Hasty, A., Bornfeldt, K., Tabas, I., Tall, A.R.  Defective phagocytosis of apoptotic cells by ob/ob peritoneal and atherosclerotic lesional macrophages:  reversal of defects by PPARg/d activation and fish oils.  Submitted for publication.

Seimon, T., Wang, Y., Kuriakose, G., Han, S., Senokuchi, T., Tall, A., Tabas, I. 2009. Deficiency of p38a in macrophages promotes apoptosis and plaque necrosis in advanced murine atherosclerotic lesions.  J. Clin. Invest. 119:886-898.

Sun, Y., Ishibashi, M., Seimon, T., Sharma, S.M., Fitzgerald, K.A., Samokhin, A.O., Wang. Y., Sayers, S., Aikawa, M., Jerome, G.W., Ostrowski, M.C., Bromme, D., Libby. P., Tabas, I., Welch, C.L., Tall, A.R. 2009. Free cholesterol accumulation in macrophage membranes activates Toll-like receptors, p38 MAP kinase and induces cathepsin K.  Circulation Res., 104:455-465.

Thorp, E., Li, G., Seimon, T.A., Kuriakose, G., Ron, D., Tabas, I. 2009. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metabolism, 9:474-481.

Timmins, J., Ozcan, L., Seimon, T.A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E.N., Anderson, M.E., and Tabas, I. 2009. Calcium/calmodulin-dependent protein kinase II links endoplasmic reticulum stress with Fas and mitochondrial apoptosis pathways.  In revision for J. Clin. Invest..

Tam, C., Idone, V., Devlin, C., Tabas, I., Andrews, N.W. 2009. Exocytosis of acid sphingomyelinase upon cell injury triggers endocytosis and plasma membrane repair. In revision for Science.

Li, G., Mongillo, M., Chin, K-T., Harding, H., Ron, D., Marks, A.R., and Tabas, I. 2009. Role of ERO1a-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis.  In revision for J. Cell Biol.

Manning-Tobin, J.J., Moore. K.J., Seimon, T.A., Bell, S.A., Sharuk, M., Alvarez-Leite, J.I., de Winther, M.P.J., Tabas, I., Freeman, M.W. 2009. Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice.  Arterio. Thromb. Vasc. Biol. 29:19-26.
             

Devlin, C.M., Leventhal, A.R., Kuriakose, G., Schuchman, E.H., Williams, K.J., Tabas, I. 2008. Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression.  Arterio. Thromb. Vasc. Biol.  20:2607-2613.

Thorp, E., Li, Y., Bao, L., Yao, P.M., Kuriakose, G., Rong, J., Fisher, E.A., Tabas, I. 2008. Increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2.  Arterio. Thromb. Vasc. Biol.  29:169-72.

Packard, R.R.S., Tabas, I., Libby, P., Lichtman, A.H. 2008. CD11c+ dendritic cells maintain antigen processing, presentation capabilities, and CD4+.  Circulation Res.103:965-973.

Li, Y., Zhang, Y., Dorweiler, B., Cui, D., Wang, T., Woo, C.W., Wolberger, C., Imai, S., Tabas, I. 2008. Extracellular Nampt protects macrophages from ER stress-induced apoptosis via a non-enzymatic interleukin-6/STAT3 signaling mechanism.  J. Biol. Chem. 283:34833–34843.

Thorp, E., Li, G., Kuriakose, G., Ron, D., and Tabas, I.  2008. Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- mice lacking CHOP.  Submitted for publication.

Senokuchi, T., Liang, C.P., Seimon, T.A., Han, S., Matsumoto, M., Paik, J.H., DePinho, R.A., Accili, D., Tabas, I., and Tall, A.R. 2008. FoxOs promote apoptosis of insulin resistant macrophages during cholesterol-induced ER stress.  Submitted for publication.

Iqbal, J., Dai, K., Seimon, T.A., Jungreis, R., Oyadomari, M., Ron, D., Tabas, I., and Hussain, M. 2008. IRE1β restricts chylomicron production by selectively degrading MTP mRNA.  In revision for Cell Metabolism.

Thorp, E., Cui, D., Kuriakose, G., and Tabas, I. 2008.  Mutation of the Mertk receptor promotes apoptotic cell accumulation and plaque necrosis in advanced atherosclerotic lesions of apolipoprotein E-deficient mice.  Submitted for publication. 

Lim, W., Timmins, J., Seimon, T.A., Sadler, A., Kolodgie, F., Virmani, R., Schindler, C., and Tabas, I. 2008. A pathway involving calcium/calmodulin-dependent protein kinase II and serine-phosphorylated Stat1 is critical for endoplasmic reticulum stress-dependent macrophage apoptosis.  A new component of the multi-hit model of macrophage death relevant to advanced atherosclerosis.  Circulation, In press. 

Klionsky, D., et al. 2008. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:2-25.

Li, Y., and Tabas, I. 2007. The inflammatory cytokine response of cholesterol-enriched macrophages is suppressed by stimulated pinocytosis. J. Leukoc. Biol. 81: 483–491. 

Tabas, I.  2007. Lipid and atherosclerosis. IN Biochemistry of Lipids, Lipoproteins, and Membranes (Vance, D.E. and Vance, J., eds.), Elsevier, Amsterdam.  5th Edition, In press.

Cui, D., Thorp, E., Li, Y., Wang, N., Yvan-Charvet, L., Tall, A.R., and Tabas, I.  2007.  Pivotal Advance:  Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells.  J. Leukoc. Biol. 82:1040-50.

Bao, S., Li, Y., Leia, X., Wohltmanna, M., Bohrera, A., Ramanadhama, S., Tabas, I., and Turk, J.  2007. Attenuated free cholesterol loading-induced apoptosis but preserved phospholipid composition of peritoneal macrophages from mice that do not express group VIA phospholipase A2.  J. Biol. Chem. 282:27100-14.

Thorp, E., Kuriakose, G., Shah, Y.M., Gonzalez, F.J., and Tabas, I. 2007. Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of non-diabetic LDL receptor-null mice.  Circulation 116:2182-2190.

Tabas, I.  2007. Macrophage death, plaque necrosis, and insulin resistance.  Clin. Invest. Arterioscl. Suppl. 3, 53-55.

Tabas, I.  2007. Apoptosis and efferocytosis in mouse models of atherosclerosis. Current Drug Targets 8:1288-1296.

Tabas, I., Williams, K.J., Borén, J. 2007. Subendothelial lipoprotein retention as the initiating process in atherosclerosis. Update and therapeutic implications. Circulation 116:1832-44.

Tabas, I., Seimon, T., Arrelano, J., Li, Y., Forcheron, F., Cui, D., Han, S., Liang, C.P., Tall, A., Accili, D.  2007. The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis.  IN Fatty Acids and Lipotoxicity in Obesity and Diabetes.  Novartis Foundation Symposium 286.  John Wiley & Sons, Ltd., Chichester, UK, pp. 99-112.

Tabas, I. 2007. Clinical and mechanistic links between diabetes and heart disease.  Medscape online:  http://www.medscape.com/viewarticle/566297.

Li, Y., Schwabe, R.F., DeVries-Seimon, T., Yao, P.M., Gerbod-Giannone, M.C., Tall, A.R., Davis, R.J., Flavell, R., Brenner, D.A., and Tabas, I. 2005. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem. 280, 21763-72.

Tabas, I. 2005. Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis. The Importance of Lesion Stage and Phagocytic Efficiency. Arterioscler Thromb Vasc Biol.

Devries-Seimon, T., Li, Y., Yao, P.M., Stone, E., Wang, Y., Davis, R.J., Flavell, R., and Tabas, I. 2005. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol. 171, 61-73.

Maxfield, F.R., and Tabas, I. 2005.  Role of cholesterol and lipid organization in disease. Nature 438:36-45.

Li, Y., Ge, M., Ciani, L., Kuriakose, G., Westover, E.J., Dura, M., Covey, D.F., Freed, J.H., Maxfield, F.R., Lytton, J., and Tabas, I. 2004. Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmic-endoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterol-loaded macrophages. J Biol Chem. 279, 37030-9. [view pdf]

Feng, B., Yao, P.M., Li, Y., Devlin, C.M., Zhang, D., Harding, H.P., Sweeney, M., Rong, J.X., Kuriakose, G., Fisher, E.A., Marks A.R., Ron, D, and Tabas, I. 2003. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol. 5, 781-92 [view pdf]

Feng, B., Zhang, D., Kuriakose, G., Devlin, C.M., Kockx, M., and Tabas, I. 2003. Niemann-Pick C heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis. Proc Natl Acad Sci U S A. 100, 10423-8. [view pdf]

 

Recent Honors

2014 Bonazinga award: "Presented annually to a Society of Leukocyte Biology member for excellence in leukocyte biology research. It is the highest honor the society can bestow upon one of its members and has been awarded annually since 1980."

 

Recent Reviews

Tabas, I. and Glass, C.K. (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339:166-172. PMCID:PMC3608517

Tabas, I. (2012) Cardiology: Bad matters made worse. Nature. 487:306-8. NIHMS526576 (PMC pending)

Subramanin, M. and Tabas, I. (2014) A new RIDDle in DC-mediated cross-presentation. Nature Immunol. 15:213-215.

Fredman G, Ozcan L, and Tabas I. (2014) Common therapeutic targets in cardiometabolic disease. Sci Transl Med. 6:239ps5.

 

Patents