Publications by authors named "Jasmine M F Wu"

10 Publications

  • Page 1 of 1

Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis.

Int J Mol Sci 2021 Nov 1;22(21). Epub 2021 Nov 1.

Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, 07747 Jena, Germany.

Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis.
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http://dx.doi.org/10.3390/ijms222111852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584314PMC
November 2021

The role of ceramide accumulation in human induced pluripotent stem cell-derived cardiomyocytes on mitochondrial oxidative stress and mitophagy.

Free Radic Biol Med 2021 05 9;167:66-80. Epub 2021 Mar 9.

Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, Jena, Germany.

Oversupply of fatty acids (FAs) to cardiomyocytes (CMs) is associated with increased ceramide content and elevated the risk of lipotoxic cardiomyopathy. Here we investigate the role of ceramide accumulation on mitochondrial function and mitophagy in cardiac lipotoxicity using CMs derived from human induced pluripotent stem cell (hiPSC). Mature CMs derived from hiPSC exposed to the diabetic-like environment or transfected with plasmids overexpressing serine-palmitoyltransferase long chain base subunit 1 (SPTLC1), a subunit of the serine-palmitoyltransferase (SPT) complex, resulted in increased intracellular ceramide levels. Accumulation of ceramides impaired insulin-dependent phosphorylation of Akt through activating protein phosphatase 2A (PP2A) and disturbed gene and protein levels of key metabolic enzymes including GLUT4, AMPK, PGC-1α, PPARα, CD36, PDK4, and PPARγ compared to controls. Analysis of CMs oxidative metabolism using a Seahorse analyzer showed a significant reduction in ATP synthesis-related O consumption, mitochondrial β-oxidation and respiratory capacity, indicating an impaired mitochondrial function under diabetic-like conditions or SPTLC1-overexpression. Further, ceramide accumulation increased mitochondrial fission regulators such as dynamin-related protein 1 (DRP1) and mitochondrial fission factor (MFF) as well as auto/mitophagic proteins LC3B and PINK-1 compared to control. Incubation of CMs with the specific SPT inhibitor (myriocin) showed a significant increase in mitochondrial fusion regulators the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) as well as p-Akt, PGC-1 α, GLUT-4, and ATP production. In addition, a significant decrease in auto/mitophagy and apoptosis was found in CMs treated with myriocin. Our results suggest that ceramide accumulation has important implications in driving insulin resistance, oxidative stress, increased auto/mitophagy, and mitochondrial dysfunction in the setting of lipotoxic cardiomyopathy. Therefore, modulation of the de novo ceramide synthesis pathway may serve as a novel therapeutic target to treat metabolic cardiomyopathy.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.02.016DOI Listing
May 2021

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium.

Int J Mol Sci 2021 Feb 2;22(3). Epub 2021 Feb 2.

Department of Internal Medicine I, University Hospital Jena, 07747 Jena, Thüringen, Germany.

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.
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http://dx.doi.org/10.3390/ijms22031498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867320PMC
February 2021

Ketone bodies for the starving heart.

Nat Metab 2020 11;2(11):1183-1185

Department of Internal Medicine I (Cardiology, Angiology and Intensive Medical Care), University Hospital Jena, Friedrich-Schiller-University Jena, Jena, Germany.

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http://dx.doi.org/10.1038/s42255-020-00310-6DOI Listing
November 2020

Cardiovascular prognosis: a new role for ceramides and other cardiometabolites.

ESC Heart Fail 2020 Oct 11. Epub 2020 Oct 11.

Division of Cardiology, Department of Internal Medicine I, University Hospital Jena, Jena, Germany.

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http://dx.doi.org/10.1002/ehf2.13025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754998PMC
October 2020

Longitudinal metabolic profiling of cardiomyocytes derived from human-induced pluripotent stem cells.

Basic Res Cardiol 2020 05 18;115(4):37. Epub 2020 May 18.

Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, FSU, FZL Haus F4, Am Klinikum 1, 07747, Jena, Germany.

Human-induced pluripotent stem cells (h-iPSCs) are a unique in vitro model for cardiovascular research. To realize the potential applications of h-iPSCs-derived cardiomyocytes (CMs) for drug testing or regenerative medicine and disease modeling, characterization of the metabolic features is critical. Here, we show the transcriptional profile during stages of cardiomyogenesis of h-iPSCs-derived CMs. CM differentiation was not only characterized by the expression of mature structural components (MLC2v, MYH7) but also accompanied by a significant increase in mature metabolic gene expression and activity. Our data revealed a distinct substrate switch from glucose to fatty acids utilization for ATP production. Basal respiration and respiratory capacity in 9 days h-iPSCs-derived CMs were glycolysis-dependent with a shift towards a more oxidative metabolic phenotype at 14 and 28 day old CMs. Furthermore, mitochondrial analysis characterized the early and mature forms of mitochondria during cardiomyogenesis. These results suggest that changes in cellular metabolic phenotype are accompanied by increased O consumption and ATP synthesis to fulfill the metabolic needs of mature CMs activity. To further determine functionality, the physiological response of h-iPSCs-derived CMs to β-adrenergic stimulation was tested. These data provide a unique in vitro human heart model for the understanding of CM physiology and metabolic function which may provide useful insight into metabolic diseases as well as novel therapeutic options.
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http://dx.doi.org/10.1007/s00395-020-0796-0DOI Listing
May 2020

Prostaglandin E Receptor 2 Modulates Macrophage Activity for Cardiac Repair.

J Am Heart Assoc 2018 10;7(19):e009216

1 Institute of Basic Medical Sciences and Institute of Clinical Medicine National Cheng Kung University Tainan Taiwan.

Background Prostaglandin E has long been known to be an immune modulator. It is released after tissue injury and plays a role in modulating macrophage activities, which are essential for tissue regeneration. However, the involvement of prostaglandin E receptor 2 ( EP 2)-dependent regulation of macrophages in postischemic heart is unclear. This study aims to evaluate the role of EP 2 in damaged heart. Methods and Results The effect of EP 2 in postischemic heart was evaluated using EP 2-deficient transgenic mice. We demonstrated that cardiac function was worse after myocardial injury on loss of EP 2. Furthermore, EP 2 deficiency also altered proinflammatory response and resulted in a defect in macrophage recruitment to the injured myocardium. Transcriptome analysis revealed that the expression of erythroid differentiation regulator 1 ( Erdr1) was significantly induced in EP 2-deficient macrophages. Knocking down Erdr1 expression restored migration ability of EP 2-deficient cells both in vitro and in vivo. By using a genetic fate-mapping approach, we showed that abolishment of EP 2 expression effectively attenuated cell replenishment. Conclusions The EP 2-dependent signaling pathway plays a critical role in regulating macrophage recruitment to the injured myocardium, thereby exerting a function in modulating the inflammatory microenvironment for cardiac repair.
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http://dx.doi.org/10.1161/JAHA.118.009216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404869PMC
October 2018

Circulating cells contribute to cardiomyocyte regeneration after injury.

Circ Res 2015 Feb 14;116(4):633-41. Epub 2014 Nov 14.

From the Institute of Basic Medical Sciences (J.M.F.W., Y.-C.H.) and Institute of Molecular Medicine (L.-W.W.), College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Surgery (C.-Y.L.) and Department of Radiation Oncology (H.-J.C.), National Cheng Kung University Hospital, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan (H.-J.C.); Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan (H.N.); and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (P.C. H.H.).

Rationale: The contribution of bone marrow-borne hematopoietic cells to the ischemic myocardium has been documented. However, a pivotal study reported no evidence of myocardial regeneration from hematopoietic-derived cells. The study did not take into account the possible effect of early injury-induced signaling as the test mice were parabiotically paired to partners immediately after surgery-induced myocardial injury when cross-circulation has not yet developed.

Objective: To re-evaluate the role of circulating cells in the injured myocardium.

Methods And Results: By combining pulse-chase labeling and parabiosis model, we show that circulating cells derived from the parabiont expressed cardiac-specific markers in the injured myocardium. Genetic fate mapping also revealed that circulating hematopoietic cells acquired cardiac cell fate by means of cell fusion and transdifferentiation.

Conclusions: These results suggest that circulating cells participate in cardiomyocyte regeneration in a mouse model of parabiosis when the circulatory system is fully developed before surgery-induced heart injury.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.304564DOI Listing
February 2015

Prostaglandin E₂ promotes post-infarction cardiomyocyte replenishment by endogenous stem cells.

EMBO Mol Med 2014 04 21;6(4):496-503. Epub 2014 Jan 21.

Institute of Basic Medical Sciences, National Cheng Kung University and Hospital, Tainan, Taiwan.

Although self-renewal ability of adult mammalian heart has been reported, few pharmacological treatments are known to promote cardiomyocyte regeneration after injury. In this study, we demonstrate that the critical period of stem/progenitor cell-mediated cardiomyocyte replenishment is initiated within 7 days and saturates on day 10 post-infarction. Moreover, blocking the inflammatory reaction with COX-2 inhibitors may also reduce the capability of endogenous stem/progenitor cells to repopulate lost cells. Injection of the COX-2 product PGE2 enhances cardiomyocyte replenishment in young mice and recovers cell renewal through attenuating TGF-β1 signaling in aged mice. Further analyses suggest that cardiac stem cells are PGE2-responsive and that PGE2 may regulate stem cell activity directly through the EP2 receptor or indirectly by modulating its micro-environment in vivo. Our findings provide evidence that PGE2 holds great potential for cardiac regeneration.
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http://dx.doi.org/10.1002/emmm.201303687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992076PMC
April 2014

Cell type-specific filamin complex regulation by a novel class of HECT ubiquitin ligase is required for normal cell motility and patterning.

Development 2011 Apr 9;138(8):1583-93. Epub 2011 Mar 9.

Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, UK.

Differential cell motility, which plays a key role in many developmental processes, is perhaps most evident in examples of pattern formation in which the different cell types arise intermingled before sorting out into discrete tissues. This is thought to require heterogeneities in responsiveness to differentiation-inducing signals that result in the activation of cell type-specific genes and 'salt and pepper' patterning. How differential gene expression results in cell sorting is poorly defined. Here we describe a novel gene (hfnA) that provides the first mechanistic link between cell signalling, differential gene expression and cell type-specific sorting in Dictyostelium. HfnA defines a novel group of evolutionarily conserved HECT ubiquitin ligases with an N-terminal filamin domain (HFNs). HfnA expression is induced by the stalk differentiation-inducing factor DIF-1 and is restricted to a subset of prestalk cells (pstO). hfnA(-) pstO cells differentiate but their sorting out is delayed. Genetic interactions suggest that this is due to misregulation of filamin complex activity. Overexpression of filamin complex members phenocopies the hfnA(-) pstO cell sorting defect, whereas disruption of filamin complex function in a wild-type background results in pstO cells sorting more strongly. Filamin disruption in an hfnA(-) background rescues pstO cell localisation. hfnA(-) cells exhibit altered slug phototaxis phenotypes consistent with filamin complex hyperactivity. We propose that HfnA regulates filamin complex activity and cell type-specific motility through the breakdown of filamin complexes. These findings provide a novel mechanism for filamin regulation and demonstrate that filamin is a crucial mechanistic link between responses to differentiation signals and cell movement in patterning based on 'salt and pepper' differentiation and sorting out.
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http://dx.doi.org/10.1242/dev.063800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062426PMC
April 2011
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