Won Hee Lee
- Assistant Professor, Basic Medical Sciences
- Assistant Professor, Clinical Translational Sciences
- Member of the Graduate Faculty
Contact
- (602) 827-2142
- AZ Biomedical Collaborative 1, Rm. 431A
- Tucson, AZ 85724
- whlee@arizona.edu
Degrees
- Ph.D.
- Virginia Tech, Blacksburg, Virginia, United States
Awards
- AZDHS New Investigator Award
- Spring 2023 (Award Nominee)
- RII Faculty Seed Grant
- UArizona’s Research, Innovation & Impact (RII) and BIO5, Summer 2022 (Award Nominee)
- AHA BCVS Abstract Travel Grant Award
- American Heart Association, Fall 2021 (Award Nominee)
- Valley Research Partnership (VRP) Program Award
- Valley Research Partnership, Summer 2021
- AHA Postdoc Fellowship
- American Heart Association, Spring 2020
Interests
No activities entered.
Courses
2023-24 Courses
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Dissertation
CTS 920 (Spring 2024) -
Dissertation
CTS 920 (Fall 2023)
2022-23 Courses
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Dissertation
CTS 920 (Spring 2023)
2021-22 Courses
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Research
CTS 900 (Spring 2022) -
Research
CTS 900 (Fall 2021)
2020-21 Courses
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Individualized Science Writing
CTS 585 (Spring 2021) -
Research
CTS 900 (Spring 2021)
Scholarly Contributions
Journals/Publications
- Jousma, J., Park, J., Han, Z., Yan, G., Nukala, S. B., Kwon, Y., Lee, W. H., Jiang, Y., & Ong, S. (2023).
Abstract P2084: Adipose Tissues Thermogenesis Provides Cardioprotection Against Diastolic Dysfunction Developed In An Obesity-Induced HFpEF Model
. Circulation Research, 133(Suppl_1). doi:10.1161/res.133.suppl_1.p2084 - Liu, C. W., Le, H. H., Denaro Iii, P., Dai, Z., Shao, N. Y., Ong, S. G., & Lee, W. H. (2023). E-cigarettes induce dysregulation of autophagy leading to endothelial dysfunction in pulmonary arterial hypertension. Stem cells (Dayton, Ohio).More infoGiven the increasing popularity of electronic cigarettes (e-cigs), it is imperative to evaluate the potential health risks of e-cigs, especially in users with preexisting health concerns such as pulmonary arterial hypertension (PAH). The aim of the present study was to investigate whether differential susceptibility exists between healthy and PAH patients to e-cig exposure and the molecular mechanisms contributing to it. Patient-specific induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from healthy individuals and PAH patients were used to investigate whether e-cig contributes to the pathophysiology of PAH and affects EC homeostasis in PAH. Our results showed that PAH iPSC-ECs showed a greater amount of damage than healthy iPSC-ECs upon e-cig exposure. Transcriptomic analyses revealed that differential expression of Akt3 may be responsible for increased autophagic flux impairment in PAH iPSC-ECs, which underlies increased susceptibility upon e-cig exposure. Moreover, knockdown of Akt3 in healthy iPSC-ECs significantly induced autophagic flux impairment and endothelial dysfunction, which further increased with e-cig treatment, thus mimicking the PAH cell phenotype after e-cig exposure. In addition, functional disruption of mTORC2 by knocking down Rictor in PAH iPSC-ECs caused autophagic flux impairment, which was mediated by downregulation of Akt3. Finally, pharmacological induction of autophagy via direct inhibition of mTORC1 and indirect activation of mTORC2 with rapamycin reverses e-cig-induced decreased Akt3 expression, endothelial dysfunction, autophagic flux impairment, and decreased cell viability and migration in PAH iPSC-ECs. Taken together, these data suggest a potential link between autophagy and Akt3-mediated increased susceptibility to e-cig in PAH.
- Nukala, S. B., Jousma, J., Yan, G., Han, Z., Kwon, Y., Cho, Y., Liu, C., Gagnon, K., Pinho, S., Rehman, J., Shao, N. Y., Ong, S. B., Lee, W. H., & Ong, S. G. (2023). Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor. Cardiovascular research.More infoNovel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored.
- Yi, D., Liu, B., Ding, H., Li, S., Li, R., Pan, J., Ramirez, K., Xia, X., Kala, M., Ye, Q., Lee, W. H., Frye, R. E., Wang, T., Zhao, Y., Knox, K. S., Glembotski, C. C., Fallon, M. B., & Dai, Z. (2023).
E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension
. Hypertension, 80(11), 2357-2371. doi:10.1161/hypertensionaha.123.21241 - Jousma, J., Han, Z., Yan, G., Nukala, S. B., Kwon, Y., Thi Le, H. H., Li, Y., Ong, S. B., Lee, W. H., & Ong, S. G. (2022). Alteration of the N6-methyladenosine epitranscriptomic profile in synthetic phthalate-treated human induced pluripotent stem cell-derived endothelial cells. Epigenomics, 14(19), 1139-1155.More infoThis study aimed to characterize the N-methyladenosine epitranscriptomic profile induced by mono(2-ethylhexyl) phthalate (MEHP) exposure using a human-induced pluripotent stem cell-derived endothelial cell model. A multiomic approach was employed by performing RNA sequencing in parallel with an N-methyladenosine-specific microarray to identify mRNAs, lncRNAs, and miRNAs affected by MEHP exposure. An integrative multiomic analysis identified relevant biological features affected by MEHP, while functional assays provided a phenotypic characterization of these effects. Transcripts regulated by the epitranscriptome were validated with quantitative PCR and methylated RNA immunoprecipitation. The authors' profiling of the epitranscriptome expands the scope of toxicological insights into known environmental toxins to under surveyed cellular contexts and emerging domains of regulation and is, therefore, a valuable resource to human health.
- Nukala, S. B., Jousma, J., Cho, Y., Lee, W. H., & Ong, S. G. (2022). Long non-coding RNAs and microRNAs as crucial regulators in cardio-oncology. Cell & bioscience, 12(1), 24.More infoCancer is one of the leading causes of morbidity and mortality worldwide. Significant improvements in the modern era of anticancer therapeutic strategies have increased the survival rate of cancer patients. Unfortunately, cancer survivors have an increased risk of cardiovascular diseases, which is believed to result from anticancer therapies. The emergence of cardiovascular diseases among cancer survivors has served as the basis for establishing a novel field termed cardio-oncology. Cardio-oncology primarily focuses on investigating the underlying molecular mechanisms by which anticancer treatments lead to cardiovascular dysfunction and the development of novel cardioprotective strategies to counteract cardiotoxic effects of cancer therapies. Advances in genome biology have revealed that most of the genome is transcribed into non-coding RNAs (ncRNAs), which are recognized as being instrumental in cancer, cardiovascular health, and disease. Emerging studies have demonstrated that alterations of these ncRNAs have pathophysiological roles in multiple diseases in humans. As it relates to cardio-oncology, though, there is limited knowledge of the role of ncRNAs. In the present review, we summarize the up-to-date knowledge regarding the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in cancer therapy-induced cardiotoxicities. Moreover, we also discuss prospective therapeutic strategies and the translational relevance of these ncRNAs.
- Joshi, S., Lee, W. H., Chen, P., Serpooshan, V., & Yang, H. (2021). Editorial: 3D Cell Culture Systems for Cardiovascular Tissue Engineering: Modelling and Regenerative Therapies. Frontiers in cardiovascular medicine, 8, 675676.
- Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., Adamopoulos, I. E., Adeli, K., Adolph, T. E., Adornetto, A., Aflaki, E., Agam, G., Agarwal, A., Aggarwal, B. B., Agnello, M., , Agostinis, P., et al. (2021). Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy, 17(1), 1-382.More infoIn 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
- Le, H. H., Liu, C. W., Denaro, P., Jousma, J., Shao, N. Y., Rahman, I., & Lee, W. H. (2021). Genome-wide differential expression profiling of lncRNAs and mRNAs in human induced pluripotent stem cell-derived endothelial cells exposed to e-cigarette extract. Stem cell research & therapy, 12(1), 593.More infoElectronic-cigarette (e-cig) usage, particularly in the youth population, is a growing concern. It is known that e-cig causes endothelial dysfunction, which is a risk factor for the development of cardiovascular diseases; however, the mechanisms involved remain unclear. We hypothesized that long noncoding RNAs (lncRNAs) may play a role in e-cig-induced endothelial dysfunction.
- Lee, W. H., Nukala, S. B., Kwon, Y., Jousma, J., Yan, G., Han, Z., Cho, Y., Shao, N., & Ong, S. (2021). Abstract 14018: lncRNA HAS2-AS1 Regulates Sunitinib-Induced Endothelial Dysfunction by Preserving the Endothelial Glycocalyx. Circulation, 144(Suppl_1). doi:10.1161/circ.144.suppl_1.14018
- Jang, H. R., Cho, H. J., Zhou, Y., Shao, N. Y., Lee, K., Le, H. H., Jeon, J., Lee, J. E., Huh, W., Ong, S. G., Lee, W. H., & Kim, Y. G. (2020). Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System. Frontiers in cell and developmental biology, 8, 618796.More infoCardiovascular complications are the leading cause of mortality in patients with chronic kidney disease (CKD). Uremic vasculopathy plays a crucial role in facilitating the progression of cardiovascular complications in advanced CKD. However, the improvement of conventional research methods could provide further insights into CKD. In this study, we aimed to develop a novel model of uremic vasculopathy as a potential drug screening system. The effects of uremic serum and different combinations of uremic toxins on induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) of a normal control and a CKD patient were investigated using several functional assays. We found that a mixture of uremic toxins composed of high urea, creatinine, uric acid, and indoxyl sulfate exerted deleterious effects on normal control iPSC-ECs that were comparable to uremic serum by increasing reactive oxygen species and apoptosis, as well as suppression of tube formation. Additional characterization revealed a potential involvement of dysregulated TGF-β signaling as treatment with either losartan or TGF-β inhibitors led to the attenuation of adverse effects induced by uremic toxins. Importantly, impaired wound healing potential seen in CKD patient-specific iPSC-ECs was rescued by treatment with losartan and TGF-β inhibitors. Our study demonstrated that simplified uremic toxin mixtures can simulate the uremic micromilieu reproducibly and CKD patient-specific iPSC-ECs can potentially recapitulate susceptibility to uremic vasculopathy. This novel model of uremic vasculopathy may provide a new research tool as a drug screening system.
- Kwon, Y., Nukala, S. B., Srivastava, S., Miyamoto, H., Ismail, N. I., Jousma, J., Rehman, J., Ong, S. B., Lee, W. H., & Ong, S. G. (2020). Detection of viral RNA fragments in human iPSC cardiomyocytes following treatment with extracellular vesicles from SARS-CoV-2 coding sequence overexpressing lung epithelial cells. Stem cell research & therapy, 11(1), 514.More infoCoronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic. The prevalence/severity of COVID-19 is higher among patients with cardiovascular risk factors. Despite the expression of angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2 infection, in cardiomyocytes, there has been no conclusive evidence of direct viral infection although the presence of viral genome within COVID-19 patients' hearts has been reported. Here, we overexpressed SARS-CoV-2 genes in A549 lung epithelial cells. We then isolated extracellular vesicles (EVs) and detected the presence of viral RNA within these EVs. We observed that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are receptive to these EVs, and viral genes were detectable in the cardiomyocytes. Accordingly, the uptake of viral RNA-harboring EVs led to an upregulation of inflammation-related genes in hiPSC-CMs. Thus, our findings indicate that SARS-CoV-2 RNA containing EVs represents an indirect route of viral RNA entry into cardiomyocytes.
- Guo, H., Tian, L., Zhang, J. Z., Kitani, T., Paik, D. T., Lee, W. H., & Wu, J. C. (2019). Single-Cell RNA Sequencing of Human Embryonic Stem Cell Differentiation Delineates Adverse Effects of Nicotine on Embryonic Development. Stem cell reports, 12(4), 772-786.More infoNicotine, the main chemical constituent of tobacco, is highly detrimental to the developing fetus by increasing the risk of gestational complications and organ disorders. The effects of nicotine on human embryonic development and related mechanisms, however, remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) of human embryonic stem cell (hESC)-derived embryoid body (EB) in the presence or absence of nicotine. Nicotine-induced lineage-specific responses and dysregulated cell-to-cell communication in EBs, shedding light on the adverse effects of nicotine on human embryonic development. In addition, nicotine reduced cell viability, increased reactive oxygen species (ROS), and altered cell cycling in EBs. Abnormal Ca signaling was found in muscle cells upon nicotine exposure, as verified in hESC-derived cardiomyocytes. Consequently, our scRNA-seq data suggest direct adverse effects of nicotine on hESC differentiation at the single-cell level and offer a new method for evaluating drug and environmental toxicity on human embryonic development in utero.
- Lee, W. H., Ong, S. G., Zhou, Y., Tian, L., Bae, H. R., Baker, N., Whitlatch, A., Mohammadi, L., Guo, H., Nadeau, K. C., Springer, M. L., Schick, S. F., Bhatnagar, A., & Wu, J. C. (2019). Modeling Cardiovascular Risks of E-Cigarettes With Human-Induced Pluripotent Stem Cell-Derived Endothelial Cells. Journal of the American College of Cardiology, 73(21), 2722-2737.More infoElectronic cigarettes (e-cigarettes) have experienced a tremendous increase in use. Unlike cigarette smoking, the effects of e-cigarettes and their constituents on mediating vascular health remain understudied. However, given their increasing popularity, it is imperative to evaluate the health risks of e-cigarettes, including the effects of their ingredients, especially nicotine and flavorings.
- Ong, S. B., Lee, W. H., Shao, N. Y., Ismail, N. I., Katwadi, K., Lim, M. M., Kwek, X. Y., Michel, N. A., Li, J., Newson, J., Tahmasebi, S., Rehman, J., Kodo, K., Jang, H. R., & Ong, S. G. (2019). Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy. Stem cell reports, 12(3), 597-610.More infoThe relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.