Ira Tabas, M.D., Ph.D.
Richard J. Stock Professor, Professor of Physiology & Cellular Biophysics, Medicine and Anatomy and Cell Biology,
Vice-Chairman of Research
The cellular and molecular biology of macrophages during atherogenesis.
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.
Gerlach, B.D., Ampomah, P.B., Yurdagul Jr., A., Liu, C., Lauring, M.C., Wang, X., Kasikara, C., Kong, N., Shi, J., Tao, W., Tabas. I. (2021) Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metabolism, 33:2445-2463. PMC8665147
Yurdagul Jr., A., Subramanian, M., Wang, X., Crown, S.B., Ilkayeva, O., Darville. L., Kolluru, G.K., Rymond, C.C., Zheng, Z., Kuriakose, G., Kevil, C.G., Koomen, J.M., Cleveland, J.L., Muoio, D.M., Tabas, I. (2020) Metabolism of apoptotic cell-derived arginine and ornithine into putrescine by macrophages promotes continual efferocytosis. Cell Metabolism 31:518-533. PMC7173557
Ghorpade, D., Ozcan, L., Zheng, Z., Nicoloro, S.M., Shen, Y., Chen, E., Blüher, M., Czech, M.P., Tabas, I. (2018) Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature 555:673-677. PMC6021131
Proto, J.D., Sozen, E., Subramanian, M., Islam , M.N., Gusarova, G., Rymond, C., Du, J., Hook, J., Kuriakose, G., Bhattacharya, J., Tabas, I. (2018) Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 49:666-677. PMC6192849
Wang, Y., Subramanian, M., Yurdagul Jr., A., Barbosa-Lorenzi, V.C., Cai, B., de Juan Sanz, J., Ryan, T.A., Nomura, M., Maxfield, F.R., Tabas, I. (2017) Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 171:331-345 PMC5679712