Won suk Jahng

All Publications

• Consequences of ionizing radiation exposure to the cardiovascular system. Nature reviews. Cardiology Jahng, J. W., Little, M. P., No, H. J., Loo, B. W., Wu, J. C. 2024

  Abstract

  Ionizing radiation is widely used in various industrial and medical applications, resulting in increased exposure for certain populations. Lessons from radiation accidents and occupational exposure have highlighted the cardiovascular and cerebrovascular risks associated with radiation exposure. In addition, radiation therapy for cancer has been linked to numerous cardiovascular complications, depending on the distribution of the dose by volume in the heart and other relevant target tissues in the circulatory system. The manifestation of symptoms is influenced by numerous factors, and distinct cardiac complications have previously been observed in different groups of patients with cancer undergoing radiation therapy. However, in contemporary radiation therapy, advances in treatment planning with conformal radiation delivery have markedly reduced the mean heart dose and volume of exposure, and these variables are therefore no longer sole surrogates for predicting the risk of specific types of heart disease. Nevertheless, certain cardiac substructures remain vulnerable to radiation exposure, necessitating close monitoring. In this Review, we provide a comprehensive overview of the consequences of radiation exposure on the cardiovascular system, drawing insights from various cohorts exposed to uniform, whole-body radiation or to partial-body irradiation, and identify potential risk modifiers in the development of radiation-associated cardiovascular disease.

  View details for DOI 10.1038/s41569-024-01056-4

  View details for PubMedID 38987578

  View details for PubMedCentralID 9512240

• The role of metabolism in directed differentiation versus trans-differentiation of cardiomyocytes. Seminars in cell & developmental biology Jahng, J. W., Zhang, M., Wu, J. C. 2021

  Abstract

  The advent of induced pluripotent stem cells (iPSCs) and identification of transcription factors for cardiac reprogramming have raised hope to cure heart disease, the leading cause of death in the world. Our knowledge in heart development and molecular barriers of cardiac reprogramming is advancing, but many hurdles are yet to be overcome for clinical translation. Importantly, we lack a full understanding of molecular mechanisms governing cell fate conversion toward cardiomyocytes. In this review, we will discuss the role of metabolism in directed differentiation versus trans-differentiation of cardiomyocytes. Cardiomyocytes exhibit a unique metabolic feature distinct from PSCs and cardiac fibroblasts, and there are multiple overlapping molecular mechanisms underlying metabolic reprogramming during cardiomyogenesis. We will discuss key metabolic changes occurring during cardiomyocytes differentiation from PSCs and cardiac fibroblasts, and the potential role of metabolic reprogramming in the enhancement strategies for cardiomyogenesis. Only when such details are discovered will more effective strategies to enhance the de novo production of cardiomyocytes be possible.

  View details for DOI 10.1016/j.semcdb.2021.05.018

  View details for PubMedID 34074592

• Beta-Adrenergic Stimulation and MYH7 G256E Mutant Gene Dosage Drive Hypertrophic Cardiomyopathy Phenotype Penetrance. bioRxiv : the preprint server for biology Heinrich, P., Jung, R. M., Achter, J. S., Nguyen, V. X., Lee, C. A., Sailer, C., Domian, H., Vander Roest, A., Suchy, F. P., Jahng, J. W., Kojic, A., Lee, D., Paasche, A., Roberts, B., Nakauchi, H., Zhu, H., Wu, J. C., Bernstein, D., Moretti, A., Lundby, A., Lee, S., Wu, S. M. 2026

  Abstract

  Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic heart disorder, characterized by significant phenotypic variability even among individuals with identical MYH7 mutations. This study aims to elucidate factors contributing to this variability and identify drivers of phenotype penetrance. We compared the baseline phenotypes of a highly penetrant MYH7 H251N mutation and the variably penetrant MYH7 G256E mutation and investigated the impact of adding beta-adrenergic stimulation and homozygosity on disease phenotype penetrance using cardiomyocytes from an isogenic line of human induced pluripotent stem cells (hiPSC-CMs).Isogenic hiPSCs with MYH7 H251N and MYH7 G256E mutations were generated using CRISPR/Cas9 technology and differentiated into cardiomyocytes (CMs). Single-cell RNA sequencing (scRNAseq) and functional analysis of contractile function revealed consistent HCM phenotype presentation in H251N CMs, whereas G256E CMs exhibited a subtle and more variable phenotype. Beta-adrenergic stimulation induced a distinct metabolic stress response in G256E CMs, characterized by impaired mitochondrial ATP upregulation. Increasing mutant gene dosage from hetero- to homozygosity led to consistent increase in hypertrophic and structural gene expression changes in G256E CMs at RNA and protein levels. These changes were distinct from the changes observed with stress response. Importantly, homozygous G256E CMs exhibited a hypercontractile functional and disorganized structural phenotype. Across multiple experimental conditions, we identified consistent increase in cardiomyocyte specific transcriptomic markers such as NPPB, APOE, PDLIM3 and ANKRD1.Our study highlights the use of a variably penetrant MYH7 mutation to investigate factors that influence HCM phenotype penetrance. Specifically, we found that mutant gene dosage and beta-adrenergic stimulation induce distinct HCM disease phenotypes, providing novel insights into mechanisms that may contribute to variable disease expression in HCM.

  View details for DOI 10.64898/2026.06.02.729411

  View details for PubMedID 42282692

  View details for PubMedCentralID PMC13252407

• Colocalization and functional analyses identify GBE1 as a gene linking muscle strength and cardiometabolic fitness. American journal of physiology. Endocrinology and metabolism Schnurr, T. M., Johnson, M. L., Jin, C., Sørensen, K. V., Kim, L., Jahng, J. W., Ramste, A., Bielczyk-Maczynska, E., Gloudemans, M. J., Saliba-Gustafsson, P., Vinton, E., Jurney, P. L., Carcamo-Orive, I., Ashley, E., Hansen, T., Knowles, J. W., Palmisano, B. T. 2026

  Abstract

  Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium (LD)-adjusted colocalization analysis of genome-wide association study (GWAS) summary statistics for handgrip strength combined with expression and splicing quantitative trait loci from skeletal muscle and identified Glycogen branching enzyme 1 (GBE1) as a candidate gene for handgrip strength. CRISPRi knockdown of GBE1 in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of GBE1 led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of GBE1 knockdown cells identified up-regulation of the human superoxide dismutase 2 (SOD2) and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize GBE1 as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.

  View details for DOI 10.1152/ajpendo.00470.2025

  View details for PubMedID 41697796

• Inhibition of CXCL10 and IFN-γ ameliorates myocarditis in preclinical models of SARS-CoV-2 mRNA vaccination. Science translational medicine Cao, X., Manhas, A., Chen, Y. I., Caudal, A., Mondejar-Parreño, G., Zhu, W., Liu, W., Kong, X., Zeng, W., Liu, L., Zhao, S. R., Jahng, J. W., Utz, P. J., Nadeau, K. C., Nishiga, M., Wu, J. C. 2025; 17 (828): eadq0143

  Abstract

  Messenger RNA (mRNA) vaccines against SARS-CoV-2 are highly effective and were instrumental in curbing the COVID-19 pandemic. However, rare cases of noninfective myocarditis, particularly in young males and typically after the second dose, have been observed. Here, we explore the mediators of this myocarditis to better understand and to enhance the safety of future mRNA vaccines. Through analysis of human plasma data and in vitro experiments with human macrophages and T cells, we identified increased C-X-C motif chemokine ligand 10 (CXCL10) and interferon-γ (IFN-γ) after exposure to BNT162b2 (Pfizer) or mRNA-1273 (Moderna). Neutralization of CXCL10 and IFN-γ during the second dose (21 days after the first dose) reduced vaccine-induced cardiac injury in mice. Neutralization also reduced cardiac stress markers such as the release of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and expression of inflammatory genes in human induced pluripotent stem cell (iPSC)-derived cardiac spheroids. When exposed to these cytokines in vitro, human iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired contractility, arrhythmogenicity, and proinflammatory gene expression patterns. Genistein, a phytoestrogen implicated in reducing cardiovascular inflammation, mitigated these effects in iPSC-CMs. In mice exposed to these cytokines or receiving BNT162b2 vaccination, genistein treatment reduced cardiac injury markers and attenuated infiltration of neutrophils and macrophages into the heart. These findings implicate CXCL10-IFN-γ signaling as a contributor to myocardial injury in experimental models of mRNA vaccination and indicate that pharmacologic modulation, such as with genistein, may mitigate cytokine-driven injury.

  View details for DOI 10.1126/scitranslmed.adq0143

  View details for PubMedID 41370400

• Age-related microbiome metabolites alter RNA splicing and chromatin accessibility in the brain. bioRxiv : the preprint server for biology Chakraborty, M., Shi, S. M., Porter, I. E., Richard, D. J., Marinov, G. K., Moore, A. A., Blum, J. L., Natarajan, A., Jahng, J. W., Wu, J. C., Lu, S. X., Davidson, S. M., Greenleaf, W. J., Saw, N. L., Shamloo, M., Brunet, A., Wyss-Coray, T., Bhatt, A. S. 2025

  Abstract

  The gut microbiome generates diverse metabolites that can enter the bloodstream and alter host biology, including brain function. Hundreds of physiologically relevant, gut-brain signaling molecules likely exist; however, there has been no systematic, high-throughput effort to identify and validate them. Here, we integrate computational, in vitro, and in vivo approaches to pinpoint microbiome-derived metabolites whose blood levels change during aging, and that induce corresponding changes in the mouse brain. First, we mine large-scale metabolomics datasets from human cohorts (each n ≥ 1200) to identify 30 microbiome-associated metabolites whose blood levels change with age. We then screen this panel in an in vitro transcriptomic assay to identify metabolites that perturb genes linked to age-related neurodegeneration. We then test four metabolites in an acute-exposure mouse model, and use multi-omic approaches to evaluate their impact on cellular functions in the brain. We confirm the known neurodegeneration-promoting effects of trimethylamine N-oxide (TMAO), including mitochondrial dysfunction, and further discover its disruptive impact on the pathways of glycolysis, GABAergic signaling, and RNA splicing. Additionally, we identify glycodeoxycholic acid (GDCA), a microbiome-derived secondary bile acid, as a potent regulator of chromatin accessibility and suppressor of genes that protect the brain from age-related, neurodegeneration-promoting insults. GDCA also acutely reduces mobility. In summary, we present a scalable framework for linking microbiome metabolites to host pathologies, and apply it to identify microbial metabolites that induce molecular changes related to neurodegeneration.

  View details for DOI 10.1101/2025.10.03.680371

  View details for PubMedID 41256397

  View details for PubMedCentralID PMC12621679

• Investigating the Risk of Arrhythmogenesis Associated With Fentanyl Abuse Using Human and Mouse Cardiomyocytes. Circulation Mondéjar-Parreño, G., Zhao, S. R., Cao, X., Liu, Y., Yang, J. Y., Jahng, J. W., Leitz, J., Wu, D., Sayed, N., Jalife, J., Wu, J. C. 2025; 152 (8): 563-566

  View details for DOI 10.1161/CIRCULATIONAHA.123.068560

  View details for PubMedID 40854017

• Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis. Nature Cho, S., Rhee, S., Madl, C. M., Caudal, A., Thomas, D., Kim, H., Kojic, A., Shin, H. S., Mahajan, A., Jahng, J. W., Wang, X., Thai, P. N., Paik, D. T., Wang, M., Mullen, M., Baker, N. M., Leitz, J., Mukherjee, S., Winn, V. D., Woo, Y. J., Blau, H. M., Wu, J. C. 2025

  Abstract

  Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.

  View details for DOI 10.1038/s41586-025-08945-9

  View details for PubMedID 40307543

  View details for PubMedCentralID 5749528

• Generation of two induced pluripotent stem cell lines to model and investigate diseases affecting Pacific Islanders. Stem cell research Zhang, A., Jahng, J. W., Guevara, J. V., Yan, C. D., McConnell, M. V., Wu, J. C. 2025; 83: 103668

  Abstract

  Pacific Islanders (PI) comprise only 0.4% of the US population, yet they have amongst the highest prevalence of diseases. They are historically underreported in medical literature and underrepresented in clinical investigation. Increased representation in clinical datasets can mitigate disparities and address differential health outcomes. In recent years, induced pluripotent stem cells (iPSCs) have become a popular platform for disease and drug investigation. Here, we generate two iPSC lines from the peripheral blood mononuclear cells (PBMCs) of healthy PI patients. We demonstrate that the lines exhibit normal morphology and karyotypes, robust expression of pluripotent markers, and the capacity for trilineage differentiation.

  View details for DOI 10.1016/j.scr.2025.103668

  View details for PubMedID 39914018

• Laminin: guardian against DNA damage by transcription stress. Cardiovascular research Jahng, J. W., Wu, J. C. 2024

  View details for DOI 10.1093/cvr/cvae122

  View details for PubMedID 38887919

• Generation of induced pluripotent stem cell lines from patients with LQT1 caused by heterozygous mutations in the KCNQ1 gene. Stem cell research Ren, L., Jahng, J. W., Belbachir, N., Cook, Z., Rivero, G. C., Perez, M. V., Wu, J. C. 2024; 78: 103443

  Abstract

  Long QT Syndrome (LQTS) is a genetic heart disorder that can induce cardiac arrhythmias. The most prevalent subtype, LQT1, stems from rare variants in the KCNQ1 gene. Utilizing induced pluripotent stem cells (iPSCs) enables detailed cellular studies and personalized medicine approaches for this life-threatening condition. We generated two LQT1 iPSC lines with single nucleotide nonsense mutations, c.1031 C>T and c.1121T>A in KCNQ1. Both lines exhibited typical iPSC morphology, expressed high levels of pluripotent markers, maintained normal karyotype, and possessed the capability to differentiate into three germ layers. These cell lines serve as important tools for investigating the biological mechanisms underlying LQT1 due to mutations in the KCNQ1 gene.

  View details for DOI 10.1016/j.scr.2024.103443

  View details for PubMedID 38763038

• Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated mitochondrial respiration. Proceedings of the National Academy of Sciences of the United States of America Lee, S., Vander Roest, A. S., Blair, C. A., Kao, K., Bremner, S. B., Childers, M. C., Pathak, D., Heinrich, P., Lee, D., Chirikian, O., Mohran, S. E., Roberts, B., Smith, J. E., Jahng, J. W., Paik, D. T., Wu, J. C., Gunawardane, R. N., Ruppel, K. M., Mack, D. L., Pruitt, B. L., Regnier, M., Wu, S. M., Spudich, J. A., Bernstein, D. 2024; 121 (19): e2318413121

  Abstract

  Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the β-myosin heavy chain (MYH7) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the MYH7 G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.

  View details for DOI 10.1073/pnas.2318413121

  View details for PubMedID 38683993

• Elucidating effects of the environmental pollutant benzo[a]pyrene [BaP] on cardiac arrhythmogenicity. Journal of molecular and cellular cardiology Yang, J. Y., Mondéjar-Parreño, G., Jahng, J. W., Lu, Y., Hamburg, N., Nadeau, K. C., Conklin, D. J., Liao, R., Chandy, M., Wu, J. C. 2024; 191: 23-26

  View details for DOI 10.1016/j.yjmcc.2024.04.013

  View details for PubMedID 38648962

• Ischemia-induced cardiac dysfunction is exacerbated in adiponectin-knockout mice due to impaired autophagy flux CTS-CLINICAL AND TRANSLATIONAL SCIENCE Sung, H., Tang, J., Jahng, J., Song, E., Chan, Y., Lone, A., Peterson, J., Abdul-Sater, A., Sweeney, G. 2024; 17 (3): e13758

  Abstract

  Strategies to enhance autophagy flux have been suggested to improve outcomes in cardiac ischemic models. We explored the role of adiponectin in mediating cardiac autophagy under ischemic conditions induced by permanent coronary artery ligation. We studied the molecular mechanisms underlying adiponectin's cardio-protective effects in adiponectin knockout (Ad-KO) compared with wild-type (WT) mice subjected to ischemia by coronary artery ligation and H9c2 cardiomyocyte cell line exposed to hypoxia. Systemic infusion of a cathepsin-B activatable near-infrared probe as a biomarker for autophagy and detection via noninvasive three-dimensional fluorescence molecular tomography combined with computerized tomography to quantitate temporal changes, indicated increased activity in the myocardium of WT mice after myocardial infarction which was attenuated in Ad-KO. Seven days of ischemia increased myocardial adiponectin accumulation and elevated ULK1/AMPK phosphorylation and autophagy assessed by Western blotting for LC3 and p62, an outcome not observed in Ad-KO mice. Cell death, assessed by TUNEL analysis and the ratio of Bcl-2:Bax, plus cardiac dysfunction, measured using echocardiography with strain analysis, were exacerbated in Ad-KO mice. Using cellular models, we observed that adiponectin stimulated autophagy flux in isolated primary adult cardiomyocytes and increased basal and hypoxia-induced autophagy in H9c2 cells. Real-time temporal analysis of caspase-3/7 activation and caspase-3 Western blot indicated that adiponectin suppressed activation by hypoxia. Hypoxia-induced mitochondrial reactive oxygen species production and cell death were also attenuated by adiponectin. Importantly, the ability of adiponectin to reduce caspase-3/7 activation and cell death was not observed in autophagy-deficient cells generated by CRISPR-mediated deletion of Atg7. Collectively, our data indicate that adiponectin acts in an autophagy-dependent manner to attenuate cardiomyocyte caspase-3/7 activation and cell death in response to hypoxia in vitro and ischemia in mice.

  View details for DOI 10.1111/cts.13758

  View details for Web of Science ID 001188734900001

  View details for PubMedID 38515365

  View details for PubMedCentralID PMC10958170

• Extracellular Vesicles Derived FromEntamoeba histolyticaHave an Immunomodulatory Effect on THP-1 Macrophages. Journal of parasitology research Chowdhury, D., Sharma, M., Jahng, J. W., Singh, U. 2024; 2024: 7325606

  Abstract

  Recent studies have shown that extracellular vesicles (EVs) secreted by various parasites are capable of modulating the host's innate immune responses, such as by altering macrophage (Mϕ) phenotypes and functions. Studies have shown that Mϕ promote early host responses to amoebic infection by releasing proinflammatory cytokines that are crucial to combating amoebiasis. Here, we are reporting for the first time the effect of EVs released by Entamoeba histolytica (EhEVs) on human THP-1 differentiated Mϕ (THP-1 Mϕ). We show that the EhEVs are internalized by THP-1 Mϕ which leads to differential regulation of various cytokines associated with both M1 and M2 Mϕ. We also saw that EhEV treatment thwarted Type 2 immune-response-related transcriptome pSTAT6 in the THP-1 Mϕ. Furthermore, EhEVs stimulated Mϕ to reduce their energy demand by suppressing oxidative phosphorylation (OXPHOS) and adenosine triphosphate (ATP) production. Hence, the human parasite E. histolytica-derived EVs are capable of eliciting an immune response from Mϕ that may contribute to overall infection status.

  View details for DOI 10.1155/2024/7325606

  View details for PubMedID 39502090

• Generation of two induced pluripotent stem cell lines from patients suffering from pulmonary hypertension. Stem cell research Chen, G., Orozco, L., Parmisano, S., Jahng, J. W., Vera, C. D., Zhuge, Y., Wu, J. C., Obal, D. 2023; 72: 103218

  Abstract

  Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease, with an estimated 500-1000 new cases diagnosed every year. A portion of these cases may be caused by mutations in the BMPR2 gene, suggesting a possible genetic component in the development of the disease. Here, we report two human induced pluripotent stem cell (iPSC) lines generated from IPAH patients. Both cell lines provide valuable insight into the molecular and cellular mechanisms of IPAH and can be used to further understand the disease.

  View details for DOI 10.1016/j.scr.2023.103218

  View details for PubMedID 37804546

• SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant. Science translational medicine Guo, H., Yu, X., Liu, Y., Paik, D. T., Justesen, J. M., Chandy, M., Jahng, J. W., Zhang, T., Wu, W., Rwere, F., Zhao, S. R., Pokhrel, S., Shivnaraine, R. V., Mukherjee, S., Simon, D. J., Manhas, A., Zhang, A., Chen, C. H., Rivas, M. A., Gross, E. R., Mochly-Rosen, D., Wu, J. C. 2023; 15 (680): eabp9952

  Abstract

  The common aldehyde dehydrogenase 2 (ALDH2) alcohol flushing variant known as ALDH2*2 affects ∼8% of the world's population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell-derived ECs (iPSC-ECs) and CRISPR-Cas9-corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*2-induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure. We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated ALDH2*2-associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2-mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na+/H+-exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate ALDH2*2-induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.

  View details for DOI 10.1126/scitranslmed.abp9952

  View details for PubMedID 36696485

• Ferroptosis of Pacemaker Cells in COVID-19. Circulation research Nishiga, M., Jahng, J. W., Wu, J. C. 2022; 130 (7): 978-980

  View details for DOI 10.1161/CIRCRESAHA.122.320951

  View details for PubMedID 35357897

• Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem cell research Manhas, A., Jahng, J. W., Vera, C. D., Shenoy, S. P., Knowles, J. W., Wu, J. C. 2022; 61: 102774

  Abstract

  Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by a thick left ventricular wall and an increased risk of arrhythmias, heart failure, and sudden cardiac death. The MYBPC3 and PRAKG2 are known causal genes for HCM. Here we generated two human-induced pluripotent stem cell lines from two HCM patients carrying two heterozygous mutations in MYBPC3 (c.459delC) and PRKAG2 (c.1703C > T). Both iPSC lines expressed pluripotent markers, had a normal karyotype, and were able to differentiate into three germ layers, making them potentially valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to these two variants.

  View details for DOI 10.1016/j.scr.2022.102774

  View details for PubMedID 35413566

• Cardiac reprogramming via chromatin remodeling by CRISPR activation. Molecular therapy : the journal of the American Society of Gene Therapy Jahng, J. W., Wu, J. C. 1800

  View details for DOI 10.1016/j.ymthe.2021.12.005

  View details for PubMedID 34895515

• Generation of three induced pluripotent stem cell lines (SCVIi014-A, SCVIi015-A, and SCVIi016-A) from patients with LQT1 caused by heterozygous mutations in the KCNQ1 gene. Stem cell research Zhang, H., Jahng, J. W., Liu, Y., Chase, A. J., Perez, M. V., Wu, J. C. 2021; 55: 102492

  Abstract

  Congenital long QT syndrome type 1 (LQT1) results from KCNQ1 mutations that cause loss of Kv7.1 channel function, leading to arrhythmias, syncope, and sudden cardiac death. Here, we generated three human-induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of LQT1 patients carrying pathogenic variants (c.569 G>A, c.585delG, and c.573_577delGCGCT) in KCNQ1. All lines show typical iPSC morphology, high expression of pluripotent markers, normal karyotype, and are able to differentiate into three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of LQT1 caused by KCNQ1 mutations.

  View details for DOI 10.1016/j.scr.2021.102492

  View details for PubMedID 34411974

• Generation of three induced pluripotent stem cell lines from hypertrophic cardiomyopathy patients carrying MYH7 mutations. Stem cell research Cao, X., Jahng, J. W., Lee, C., Zha, Y., Wheeler, M. T., Sallam, K., Wu, J. C. 2021; 55: 102455

  Abstract

  MYH7 heterozygous mutations are common genetic causes of hypertrophic cardiomyopathy (HCM). HCM is characterized by hypertrophy of the left ventricle and diastolic dysfunction. We generated three human induced pluripotent stem cell (iPSC) lines from three HCM patients each carrying a single heterozygous mutation in MYH7, c.2167C>T, c.4066G>A, and c.5135G>A, respectively. All lines expressed high levels of pluripotent markers, had normal karyotype, and possessed capability of differentiation into derivatives of the three germ layers, which can serve as valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to MYH7 mutations.

  View details for DOI 10.1016/j.scr.2021.102455

  View details for PubMedID 34352619

• Generation of three heterozygous KCNH2 mutation-carrying human induced pluripotent stem cell lines for modeling LQT2 syndrome. Stem cell research Mondejar-Parreno, G., Jahng, J. W., Belbachir, N., Wu, B. C., Zhang, X., Perez, M. V., Badhwar, N., Wu, J. C. 2021; 54: 102402

  Abstract

  Congenital long QT syndrome type 2 (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function which can lead to arrhythmias, syncope, and sudden death. Here, we generated three human-induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of two LQT2 patients carrying pathogenic variants (c.1714G>A and c.2960del) and one LQT2 patient carrying a variant of uncertain significance (c.1870A>T) in KCNH2. All lines show typical iPSC morphology, high expression of pluripotent markers, normal karyotype, and differentiate into three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of LQTS caused by caused by KCNH2 mutations.

  View details for DOI 10.1016/j.scr.2021.102402

  View details for PubMedID 34051449

• Generation of three induced pluripotent stem cell lines, SCVIi003-A, SCVIi004-A, SCVIi005-A, from patients with ARVD/C caused by heterozygous mutations in the PKP2 gene. Stem cell research Jahng, J. W., Black, K. E., Liu, L., Bae, H. R., Perez, M., Ashley, E. A., Sallam, K., Wu, J. C. 2021; 53: 102284

  Abstract

  Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease which can cause life-threatening ventricular arrhythmias and cardiac dysfunction. The autosomal dominant form of ARVD/C is caused by mutations in the cardiac desmosome, such as those in the plakoglobin plakophilin-2 (PKP2) gene. Here, we generated three human induced pluripotent stem cell (iPSC) lines from the peripheral blood mononuclear cells (PBMCs) of three ARVD/C patients carrying pathogenic variants in their PKP2 genes (c.2065_2070delinsG; c.235C>T; c.1725_1728dup). All lines show the typical morphology of pluripotent stem cells, demonstrate high expression of pluripotent markers, display normal karyotype, and differentiate into all three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of ARVD/C caused by PKP2 mutation.

  View details for DOI 10.1016/j.scr.2021.102284

  View details for PubMedID 33743362

• Generation of two heterozygous MYBPC3 mutation-carrying human iPSC lines, SCVIi001-A and SCVIi002-A, for modeling hypertrophic cardiomyopathy. Stem cell research Liu, L., Shenoy, S. P., Jahng, J. W., Liu, Y., Knowles, J. W., Zhuge, Y., Wu, J. C. 2021; 53: 102279

  Abstract

  Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that can cause sudden cardiac death and heart failure. HCM often arises from mutations in sarcomeric genes, among which the MYBPC3 is the most frequently mutated. Here we generated two human induced pluripotent stem cell (iPSC) lines from a HCM patient who has a familial history of HCM and his daughter who carries the pathogenic non-coding mutation. All lines show the typical morphology of pluripotent cells, a high expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers. These lines provide a valuable resource for studying the molecular basis of HCM and drug screening for HCM.

  View details for DOI 10.1016/j.scr.2021.102279

  View details for PubMedID 33743363

• Tumor Repressor Circular RNA as a New Target for Preventative Gene Therapy Against Doxorubicin-Induced Cardiotoxicity. Circulation research Jahng, J. W., Liu, L. n., Wu, J. C. 2020; 127 (4): 483–85

  View details for DOI 10.1161/CIRCRESAHA.120.317568

  View details for PubMedID 32762533

• Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure CIRCULATION-HEART FAILURE Byrne, N. J., Matsumura, N., Maayah, Z. H., Ferdaoussi, M., Takahara, S., Darwesh, A. M., Levasseur, J. L., Jahng, J., Vos, D., Parajuli, N., El-Kadi, A. O. S., Braam, B., Young, M. E., Verma, S., Light, P. E., Sweeney, G., Seubert, J. M., Dyck, J. R. B. 2020; 13 (1): e006277

  Abstract

  Although empagliflozin was shown to profoundly reduce cardiovascular events in diabetic patients and blunt the decline in cardiac function in nondiabetic mice with established heart failure (HF), the mechanism of action remains unknown.We treated 2 rodent models of HF with 10 mg/kg per day empagliflozin and measured activation of the NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome in the heart. We show for the first time that beneficial effects of empagliflozin in HF with reduced ejection fraction (HF with reduced ejection fraction [HFrEF]; n=30-34) occur in the absence of changes in circulating ketone bodies, cardiac ketone oxidation, or increased cardiac ATP production. Of note, empagliflozin attenuated activation of the NLRP3 inflammasome and expression of associated markers of sterile inflammation in hearts from mice with HFrEF, implicating reduced cardiac inflammation as a mechanism of empagliflozin that contributes to sustained function in HFrEF in the absence of diabetes mellitus. In addition, we validate that the beneficial cardiac effects of empagliflozin in HF with preserved ejection fraction (HFpEF; n=9-10) are similarly associated with reduced activation of the NLRP3 inflammasome. Lastly, the ability of empagliflozin to reduce inflammation was completely blunted by a calcium (Ca2+) ionophore, suggesting that empagliflozin exerts its benefit upon restoring optimal cytoplasmic Ca2+ levels in the heart.These data provide evidence that the beneficial cardiac effects of empagliflozin are associated with reduced cardiac inflammation via blunting activation of the NLRP3 inflammasome in a Ca2+-dependent manner and hence may be beneficial in treating HF even in the absence of diabetes mellitus.

  View details for DOI 10.1161/CIRCHEARTFAILURE.119.006277

  View details for Web of Science ID 000508455400004

  View details for PubMedID 31957470

• Iron overload inhibits late stage autophagic flux leading to insulin resistance EMBO REPORTS Jahng, J., Alsaadi, R., Palanivel, R., Song, E., Hipolito, V., Sung, H., Botelho, R., Russell, R., Sweeney, G. 2019; 20 (10): e47911

  Abstract

  Iron overload, a common clinical occurrence, is implicated in the metabolic syndrome although the contributing pathophysiological mechanisms are not fully defined. We show that prolonged iron overload results in an autophagy defect associated with accumulation of dysfunctional autolysosomes and loss of free lysosomes in skeletal muscle. These autophagy defects contribute to impaired insulin-stimulated glucose uptake and insulin signaling. Mechanistically, we show that iron overload leads to a decrease in Akt-mediated repression of tuberous sclerosis complex (TSC2) and Rheb-mediated mTORC1 activation on autolysosomes, thereby inhibiting autophagic-lysosome regeneration. Constitutive activation of mTORC1 or iron withdrawal replenishes lysosomal pools via increased mTORC1-UVRAG signaling, which restores insulin sensitivity. Induction of iron overload via intravenous iron-dextran delivery in mice also results in insulin resistance accompanied by abnormal autophagosome accumulation, lysosomal loss, and decreased mTORC1-UVRAG signaling in muscle. Collectively, our results show that chronic iron overload leads to a profound autophagy defect through mTORC1-UVRAG inhibition and provides new mechanistic insight into metabolic syndrome-associated insulin resistance.

  View details for DOI 10.15252/embr.201947911

  View details for Web of Science ID 000483203300001

  View details for PubMedID 31441223

  View details for PubMedCentralID PMC6776927

• Iron induces insulin resistance in cardiomyocytes via regulation of oxidative stress SCIENTIFIC REPORTS Sung, H., Song, E., Sukjahng, J., Pantopoulos, K., Sweeney, G. 2019; 9: 4668

  Abstract

  Iron overload is associated with various pathological changes which contribute to heart failure. Here, we examined mechanisms via which iron alters cardiomyocyte insulin sensitivity. Treatment of primary adult and neonatal cardiomyocytes as well as H9c2 cells with iron decreased insulin sensitivity determined via Western blotting or immunofluorescent detection of Akt and p70S6K phosphorylation and glucose uptake. Using CellROX deep red or DCF-DA probes we also observed that iron increased generation of reactive oxygen species (ROS), and that pretreatment with the superoxide dismutase mimetic MnTBAP reduced ROS production and attenuated iron-induced insulin resistance. SKQ1 and allopurinol but not apocynin reduced iron-induced ROS suggesting mitochondria and xanthine oxidase contribute to cellular ROS in response to iron. Western blotting for LC3-I, LC3-II and P62 levels as well as immunofluorescent co-detection of autophagosomes with Cyto-ID and lysosomal cathepsin activity indicated that iron attenuated autophagic flux without altering total expression of Atg7 or beclin-1 and phosphorylation of mTORC1 and ULK1. This conclusion was reinforced via protein accumulation detected using Click-iT HPG labelling after iron treatment. The adiponectin receptor agonist AdipoRon increased autophagic flux and improved insulin sensitivity both alone and in the presence of iron. We created an autophagy-deficient cell model by overexpressing a dominant-negative Atg5 mutant in H9c2 cells and this confirmed that reduced autophagy flux correlated with less insulin sensitivity. In conclusion, our study showed that iron promoted a cascade of ROS production, reduced autophagy and insulin resistance in cardiomyocytes.

  View details for DOI 10.1038/s41598-019-41111-6

  View details for Web of Science ID 000461305900001

  View details for PubMedID 30874600

  View details for PubMedCentralID PMC6420583

• Lipocalin-2 (NGAL) Attenuates Autophagy to Exacerbate Cardiac Apoptosis Induced by Myocardial Ischemia JOURNAL OF CELLULAR PHYSIOLOGY Sung, H., Chan, Y., Han, M., Jahng, J., Song, E., Danielson, E., Berger, T., Mak, T. W., Sweeney, G. 2017; 232 (8): 2125-2134

  Abstract

  Lipocalin-2 (Lcn2; also termed neutrophil gelatinase-associated lipocalin (NGAL)) levels correlate positively with heart failure (HF) yet mechanisms via which Lcn2 contributes to the pathogenesis of HF remain unclear. In this study, we used coronary artery ligation surgery to induce ischemia in wild-type (wt) mice and this induced a significant increase in myocardial Lcn2. We then compared wt and Lcn2 knockout (KO) mice and observed that wt mice showed greater ischemia-induced caspase-3 activation and DNA damage measured by TUNEL than Lcn2KO mice. Analysis of autophagy by LC3 and p62 Western blotting, LC3 immunohistochemistry and transmission electron microscopy (TEM) indicated that Lcn2 KO mice had a greater ischemia-induced increase in autophagy. Lcn2KO were protected against ischemia-induced cardiac functional abnormalities measured by echocardiography. Upon treating a cardiomyocyte cell line (h9c2) with Lcn2 and examining AMPK and ULK1 phosphorylation, LC3 and p62 by Western blot as well as tandem fluorescent RFP/GFP-LC3 puncta by immunofluorescence, MagicRed assay for lysosomal cathepsin activity and TEM we demonstrated that Lcn2 suppressed autophagic flux. Lcn2 also exacerbated hypoxia-induced cytochromc c release from mitochondria and caspase-3 activation. We generated an autophagy-deficient H9c2 cell model by overexpressing dominant-negative Atg5 and found significantly increased apoptosis after Lcn2 treatment. In summary, our data indicate that Lcn2 can suppress the beneficial cardiac autophagic response to ischemia and that this contributes to enhanced ischemia-induced cell death and cardiac dysfunction. J. Cell. Physiol. 232: 2125-2134, 2017. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jcp.25672

  View details for Web of Science ID 000399973200020

  View details for PubMedID 27800610

• Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH Song, E., Jahng, J. W. S., Chong, L. P., Sung, H. K., Han, M., Luo, C., Wu, D., Boo, S., Hinz, B., Cooper, M. A., Robertson, A. A. B., Berger, T., Mak, T. W., George, I., Schulze, P., Wang, Y., Xu, A., Sweeney, G. 2017; 9 (6): 2723-2735

  Abstract

  Lipocalin-2 (also known as NGAL) levels are elevated in obesity and diabetes yet relatively little is known regarding effects on the heart. We induced pressure overload (PO) in mice and found that lipocalin-2 knockout (LKO) mice exhibited less PO-induced autophagy and NLRP3 inflammasome activation than Wt. PO-induced mitochondrial damage was reduced and autophagic flux greater in LKO mice, which correlated with less cardiac dysfunction. All of these observations were negated upon adenoviral-mediated restoration of normal lipocalin-2 levels in LKO. Studies in primary cardiac fibroblasts indicated that lipocalin-2 enhanced priming and activation of NLRP3-inflammasome, detected by increased IL-1β, IL-18 and Caspase-1 activation. This was attenuated in cells isolated from NLRP3-deficient mice or upon pharmacological inhibition of NLRP3. Furthermore, lipocalin-2 induced release of HMGB1 from cells and NLRP3-inflammasome activation was attenuated by TLR4 inhibition. We also found evidence of increased inflammasome activation and reduced autophagy in cardiac biopsy samples from heart failure patients. Overall, this study provides new mechanistic insight on the detrimental role of lipocalin-2 in the development of cardiac dysfunction.

  View details for Web of Science ID 000404548300005

  View details for PubMedID 28670364

  View details for PubMedCentralID PMC5489876

• Lipocalin-2 inhibits autophagy and induces insulin resistance in H9c2 cells MOLECULAR AND CELLULAR ENDOCRINOLOGY Chan, Y., Sung, H., Jahng, J., Kim, G., Han, M., Sweeney, G. 2016; 430 (C): 68-76

  Abstract

  Lipocalin-2 (Lcn2; also known as neutrophil gelatinase associated lipocalin, NGAL) levels are increased in obesity and diabetes and associate with insulin resistance. Correlations exist between Lcn2 levels and various forms or stages of heart failure. Insulin resistance and autophagy both play well-established roles in cardiomyopathy. However, little is known about the impact of Lcn2 on insulin signaling in cardiomyocytes. In this study, we treated H9c2 cells with recombinant Lcn2 for 1 h followed by dose- and time-dependent insulin treatment and found that Lcn2 attenuated insulin signaling assessed via phosphorylation of Akt and p70S6K. We used multiple assays to demonstrate that Lcn2 reduced autophagic flux. First, Lcn2 reduced pULK1 S555, increased pULK1 S757 and reduced LC3-II levels determined by Western blotting. We validated the use of DQ-BSA to assess autolysosomal protein degradation and this together with MagicRed cathepsin B assay indicated that Lcn2 reduced lysosomal degradative activity. Furthermore, we generated H9c2 cells stably expressing tandem fluorescent RFP/GFP-LC3 and this approach verified that Lcn2 decreased autophagic flux. We also created an autophagy-deficient H9c2 cell model by overexpressing a dominant-negative Atg5 mutant and found that reduced autophagy levels also induced insulin resistance. Adding rapamycin after Lcn2 could stimulate autophagy and recover insulin sensitivity. In conclusion, our study indicated that acute Lcn2 treatment caused insulin resistance and use of gain and loss of function approaches elucidated a causative link between autophagy inhibition and regulation of insulin sensitivity by Lcn2.

  View details for DOI 10.1016/j.mce.2016.04.006

  View details for Web of Science ID 000378457200007

  View details for PubMedID 27090568

• Crosstalk between the heart and peripheral organs in heart failure EXPERIMENTAL AND MOLECULAR MEDICINE Jahng, J., Song, E., Sweeney, G. 2016; 48: e217

  Abstract

  Mediators from peripheral tissues can influence the development and progression of heart failure (HF). For example, in obesity, an altered profile of adipokines secreted from adipose tissue increases the incidence of myocardial infarction (MI). Less appreciated is that heart remodeling releases cardiokines, which can strongly impact various peripheral tissues. Inflammation, and, in particular, activation of the nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inflammasome are likely to have a central role in cardiac remodeling and mediating crosstalk with other organs. Activation of the NLRP3 inflammasome in response to cardiac injury induces the production and secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18. In addition to having local effects in the myocardium, these pro-inflammatory cytokines are released into circulation and cause remodeling in the spleen, kidney, skeletal muscle and adipose tissue. The collective effects of various cardiokines on peripheral organs depend on the degree and duration of myocardial injury, with systematic inflammation and peripheral tissue damage observed as HF progresses. In this article, we review mechanisms regulating myocardial inflammation in HF and the role of factors secreted by the heart in communication with peripheral tissues.

  View details for DOI 10.1038/emm.2016.20

  View details for Web of Science ID 000371804100005

  View details for PubMedID 26964833

  View details for PubMedCentralID PMC4892881