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Nhat-Tu Le, PhD

Associate Professor of Cardiovascular Sciences, Academic Institute
Associate Member, Research Institute
Houston Methodist
Weill Cornell Medical College


Biography

Dr. Nhat-Tu Le earned Bachelor and Master of Science degrees in microbiology from the University of Science in Ho Chi Minh City, Vietnam.  In 2008 she completed her PhD, also in microbiology, at Sungkyungkwan University College of Pharmacy in South Korea. The focus of her PhD training was to understand the roles of the Streptococcus pneumoniae heat shock protein ClpL in pneumococcal adherence to host cells. Her first study was published in 2007, describing the effects of Streptococcus pneumoniae heat shock protein ClpL (Caseinolytic protease L) in pathogenesis and translocation of virulence factors.  Dr. Le’s postdoctoral training was under the guidance of Dr. Jun-ichi Abe at the University of Rochester studying the role of endothelial p90RSK-ERK5 complex in the heart and the vessel. Before joining Houston Methodist in July of 2017, Dr. Le was an assistant professor at MD Anderson Cancer Center since 2014.

Description of Research

Dr. Le's research focuses on mechanisms by which atherosclerotic plaques are dominantly formed in areas of blood vessel wall that are exposed to disturbed flow (d-flow) but rarely formed in areas of blood vessel wall that are exposed to laminar flow (l-flow). Previously, Dr. Le's group demonstrated that in endothelial cells (ECs), the increased p90RSK activity promotes EC activation, dysfunction, apoptosis, and senescence, all of which are acting in concert, which ultimately promotes atherosclerotic plaque formation in areas where blood vessel are exposed to d-flow. Particularly, d-flow-mediated p90RSK activation causes EC dysfunction and atherosclerosis via downregulating the anti-inflammatory and anti-atherogenic effect of ERK5, a kinase with transcriptional activity domain that also plays an important role in the anti-inflammatory effect of statins in heterotopic heart transplantation mouse model. Once activated, p90RSK binds SENP2 and phosphorylates SENP2 T368, the cellular event that triggers SENP2 nuclear export, and consequently results in the increased SUMOylation of ERK5 and p53 and thus atherosclerosis. Simultaneously, the activated p90RSK directly binds to, and phosphorylates telomeric repeat-binding factor 2-interacting protein (TERF2IP) at S205 residue, the cellular event that is required for the TERF2IP-TRF2 complex nuclear export. An unbiased transcriptome analysis demonstrated that under d-flow-mediated p90RSK activation, TERF2IP S205A phosphorylation alters the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, leading to EC activation, senescence (increased telomere shortening, p53, p21 expression, decreased telomerase induction),  apoptosis, and atherosclerosis. Recently, Dr. Le's group reported that various drugs including the combination antiretroviral therapy (cART) used in HIV therapies, ionizing radiation (IR) and ponatinib used in cancer therapies also can induce p90RSK activation, which “prime” the cells to the secondary toxicity insults, leading to the sustained chronic inflammation. Sharing the common signaling pathway with d-flow, IR and ponatinib increases ERK5 SUMOylation, promoting EC activation and inflammation, the events that are known to increase atherosclerosis. Because both d-flow and IR are strongly associated with an increased risk of atherosclerosis and cardiovascular diseases, both d-flow and IR share common signaling pathways that are involved in atherosclerosis and cardiovascular diseases, the major goal of current studies is to investigate mechanisms by which radiotherapy used in cancer treatment can lead to cardiovascular diseases even 5-10 years later. 

Areas Of Expertise

Atherosclerosis Cardio-oncology Endothelial cell function Disturbed flow
Publications

Cancer Treatment (CTCT) Promotes Oxidative Stress and Alters Monocyte/ macrophage Biology
Kotla, S, Zhang, A, Ae Ko, K, Imanishi, M, Mazhar, H, Thomas, T, Gi, Y, Vu, HT, Krishnan, S, McBeath, E, Lin, S, Kleinerman, E, Schadler, K, Fujiwara, K, Gupte, AA, Le, N-T, Hamilton, DJ & Abe, JI 2019, Free Radical Biology and Medicine, vol. 145, no. S1, pp. S134.

Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase
Kotla, S, Le, N-T, Vu, HT, Ko, KA, Gi, YJ, Thomas, TN, Giancursio, C, Lusis, AJ, Cooke, JP, Fujiwara, K & Abe, JI 2019, Metabolism: Clinical and Experimental, vol. 100, 153962. https://doi.org/10.1016/j.metabol.2019.153962

Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein
Kotla, S, Vu, HT, Ko, KA, Wang, Y, Imanishi, M, Heo, KS, Fujii, Y, Thomas, TN, Gi, YJ, Mazhar, H, Paez-Mayorga, J, Shin, JH, Tao, Y, Giancursio, CJ, Medina, JLM, Taunton, J, Lusis, AJ, Cooke, JP, Fujiwara, K, Le, N-T & Abe, JI 2019, JCI Insight, vol. 4, no. 9, e124867. https://doi.org/10.1172/jci.insight.124867

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis
Abe, J-I, Ko, KA, Kotla, S, Wang, Y, Paez-Mayorga, J, Shin, IJ, Imanishi, M, Vu, HT, Tao, Y, Leiva-Juarez, MM, Thomas, TN, Medina, JL, Won, JH, Fujii, Y, Giancursio, CJ, McBeath, E, Shin, J-H, Guzman, L, Abe, RJ, Taunton, J, Mochizuki, N, Faubion, W, Cooke, JP, Fujiwara, K, Evans, SE & Le, N-T 2019, JCI Insight, vol. 4, no. 7. https://doi.org/10.1172/jci.insight.125570

Senescent Phenotype Induced by p90RSK-NRF2 Signaling Sensitizes Monocytes and Macrophages to Oxidative Stress in HIV-Positive Individuals
Singh, MV, Kotla, S, Le, N-T, Ae Ko, K, Heo, K-S, Wang, Y, Fujii, Y, Thi Vu, H, McBeath, E, Thomas, TN, Jin Gi, Y, Tao, Y, Medina, JL, Taunton, J, Carson, N, Dogra, V, Doyley, MM, Tyrell, A, Lu, W, Qiu, X, Stirpe, NE, Gates, KJ, Hurley, C, Fujiwara, K, Maggirwar, SB, Schifitto, G & Abe, J-I 2019, Circulation, vol. 139, no. 9, pp. 1199-1216. https://doi.org/10.1161/CIRCULATIONAHA.118.036232

The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast-epithelial crosstalk
Lin, L, Shi, C, Sun, Z, Le, N-T, Abe, JI & Hu, K 2019, Journal of Biological Chemistry, vol. 294, no. 25, pp. 9901-9910. https://doi.org/10.1074/jbc.RA119.007904

MicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway
Le, N-T & Abe, JI 2018, Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 38, no. 10, pp. 2278-2280. https://doi.org/10.1161/ATVBAHA.118.311515

Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation
Paez-Mayorga, J, Chen, AL, Kotla, S, Tao, Y, Abe, RJ, He, ED, Danysh, BP, Hofmann, MCC & Le, N-T 2018, Frontiers in cardiovascular medicine, vol. 5, 125. https://doi.org/10.3389/fcvm.2018.00125

Ionizing Radiation Induces Endothelial Inflammation and Apoptosis via p90RSK-Mediated ERK5 S496 Phosphorylation
Vu, HT, Kotla, S, Ko, KA, Fujii, Y, Tao, Y, Medina, J, Thomas, T, Hada, M, Sood, AK, Singh, PK, Milgrom, SA, Krishnan, S, Fujiwara, K, Le, N-T & Abe, JI 2018, Frontiers in cardiovascular medicine, vol. 5, 23, pp. 23. https://doi.org/10.3389/fcvm.2018.00023

Regulation of Kir2.1 Function Under Shear Stress and Cholesterol Loading
Le, N-T & Abe, J-I 2018, Journal of the American Heart Association, vol. 7, no. 5. https://doi.org/10.1161/JAHA.118.008749

Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia
Ghosh, P, Kwon, H, Park, S-S, Kim, G-L, Choi, S-Y, Kim, E-H, Tran, TD-H, Seon, SH, Le, NT, Iqbal, H, Lee, S, Pyo, S & Rhee, D-K 2018, Virulence, vol. 9, no. 1, pp. 1562-1575. https://doi.org/10.1080/21505594.2018.1526529

Sub-cellular localization specific SUMOylation in the heart
Le, N-T, Martin, JF, Fujiwara, K & Abe, J-I 2017, Biochimica et Biophysica Acta - General Subjects, vol. 1863, no. 8, pp. 2041-2055. https://doi.org/10.1016/j.bbadis.2017.01.018

Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer
Lin, SC, Lee, YC, Yu, G, Cheng, CJ, Zhou, X, Chu, K, Murshed, M, Le, NT, Baseler, L, Abe, JI, Fujiwara, K, deCrombrugghe, B, Logothetis, CJ, Gallick, GE, Yu-Lee, LY, Maity, SN & Lin, SH 2017, Developmental Cell, vol. 41, no. 5, pp. 467-480.e3. https://doi.org/10.1016/j.devcel.2017.05.005

Flow signaling and atherosclerosis
Le, N-T, Sandhu, UG, Quintana-Quezada, RA, Hoang, NM, Fujiwara, K & Abe, J-I 2017, Cellular and Molecular Life Sciences, vol. 74, no. 10, pp. 1835-1858. https://doi.org/10.1007/s00018-016-2442-4

Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases
Abe, J-I, Sandhu, UG, Hoang, NM, Thangam, M, Quintana-Quezada, RA, Fujiwara, K & Le, NT 2017, Advances in Experimental Medicine and Biology, vol. 963, pp. 337-358. https://doi.org/10.1007/978-3-319-50044-7_20

Role for SUMOylation in disturbed flow-induced atherosclerotic plaque formation
Abe, JI, Le, N-T & Heo, KS 2015, Biomedical Engineering Letters, vol. 5, no. 3, pp. 162-171. https://doi.org/10.1007/s13534-015-0199-6

Platelet Extracellular Regulated Protein Kinase 5 Is a Redox Switch and Triggers Maladaptive Platelet Responses and Myocardial Infarct Expansion
Cameron, SJ, Ture, SK, Mickelsen, D, Chakrabarti, E, Modjeski, KL, McNitt, S, Seaberry, M, Field, DJ, Le, N-T, Abe, J-I & Morrell, CN 2015, Circulation, vol. 132, no. 1, pp. 47-58. https://doi.org/10.1161/CIRCULATIONAHA.115.015656

Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function
Heo, K-S, Le, N-T, Cushman, HJ, Giancursio, CJ, Chang, E, Woo, C-H, Sullivan, MA, Taunton, J, Yeh, ETH, Fujiwara, K & Abe, J 2015, The Journal of clinical investigation, vol. 125, no. 3, pp. 1299-310. https://doi.org/10.1172/JCI76453

Erratum for Le et al., Modulation of Adherence, Invasion, and Tumor Necrosis Factor Alpha Secretion during the Early Stages of Infection by Streptococcus pneumoniae ClpL
Le, N-T, Jeong, H-Y, Kwon, H-Y, Ogunniyi, AD, Paton, JC, Pyo, S-N & Rhee, D-K 2015, Infection and Immunity, vol. 83, no. 3, pp. 1224. https://doi.org/10.1128/IAI.03125-14

Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents
Le, N-T, Takei, Y, Izawa-Ishizawa, Y, Heo, K-S, Lee, H, Smrcka, AV, Miller, BL, Ko, KA, Ture, S, Morrell, C, Fujiwara, K, Akaike, M & Abe, J 2014, Journal of Immunology, vol. 193, no. 7, pp. 3803-15. https://doi.org/10.4049/jimmunol.1400571

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