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151 results on '"Perisic, Ljubica"'

1. Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype

Author

Rademakers, Timo, Manca, Marco, Jin, Han, Orban, Tanguy, Perisic, Ljubica Matic, Frissen, Hubertus J. M., Rühle, Frank, Hautvast, Petra, van Rijssel, Jos, van Kuijk, Kim, Mees, Barend M. E., Peutz-Kootstra, Carine J., Heeneman, Sylvia, Daemen, Mat J. A. P., Pasterkamp, Gerard, Stoll, Monika, van Zandvoort, Marc A. M. J., Hedin, Ulf, Dequiedt, Franck, van Buul, Jaap D., Sluimer, Judith C., and Biessen, Erik A. L.

Published
2024
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2. CDKN2B Regulates TGFβ Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels.

Author

Nanda, Vivek, Downing, Kelly P, Ye, Jianqin, Xiao, Sophia, Kojima, Yoko, Spin, Joshua M, DiRenzo, Daniel, Nead, Kevin T, Connolly, Andrew J, Dandona, Sonny, Perisic, Ljubica, Hedin, Ulf, Maegdefessel, Lars, Dalman, Jessie, Guo, Liang, Zhao, XiaoQing, Kolodgie, Frank D, Virmani, Renu, Davis, Harry R, and Leeper, Nicholas J

Subjects
Muscle, Skeletal, Muscle, Smooth, Vascular, Carotid Arteries, Coronary Vessels, Cells, Cultured, Chromosomes, Human, Pair 9, Myocytes, Smooth Muscle, Hindlimb, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Disease Models, Animal, Genetic Predisposition to Disease, Neovascularization, Pathologic, Transfection, Signal Transduction, Cell Hypoxia, RNA Interference, Neovascularization, Physiologic, Phenotype, Time Factors, Female, Male, Atherosclerosis, Cyclin-Dependent Kinase Inhibitor p15, Smad7 Protein, Transforming Growth Factor beta1, atherosclerosis, cyclin-dependent kinase inhibitor p15, genetic variation, pathologic angiogenesis, peripheral artery disease, smooth muscle cells, Cardiovascular, Aging, Genetics, 2.1 Biological and endogenous factors, Aetiology, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

RationaleGenetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown.ObjectiveTo determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis-related mechanism.Methods and resultsQuantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene, Cdkn2b. These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the Cdkn2b-deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor β (TGFβ) signaling in cultured cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient cells, as well as TGFβ1 upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of CDKN2B impairs the expression of the inhibitory factor, SMAD-7, which promotes downstream TGFβ activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule, TGFβ1-induced-1, which is a TGFβ-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro.ConclusionsThese results suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis but may also impair TGFβ signaling and hypoxic neovessel maturation.

Published
2016

11. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

Author

Kojima, Yoko, Downing, Kelly, Kundu, Ramendra, Miller, Clint, Dewey, Frederick, Lancero, Hope, Raaz, Uwe, Perisic, Ljubica, Hedin, Ulf, Schadt, Eric, Maegdefessel, Lars, Quertermous, Tom, and Leeper, Nicholas J.

Subjects
Enzyme inhibitors -- Physiological aspects, Genetic variation -- Identification and classification, Atherosclerosis -- Development and progression, Health care industry
Abstract

Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease. We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent kinase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression. Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores. Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells. As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages. These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration. The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2b-deficient cells. Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis., Introduction Traditional risk factors account for approximately half of an individual's lifetime risk of cardiovascular disease (1), (2). The balance, therefore, is accounted for by a combination of unmeasured environmental [...]

Published
2014
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13. Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases

Author

Nurnberg, Sylvia T., primary, Guerraty, Marie A., additional, Wirka, Robert C., additional, Rao, H. Shanker, additional, Pjanic, Milos, additional, Norton, Scott, additional, Serrano, Felipe, additional, Perisic, Ljubica, additional, Elwyn, Susannah, additional, Pluta, John, additional, Zhao, Wei, additional, Testa, Stephanie, additional, Park, YoSon, additional, Nguyen, Trieu, additional, Ko, Yi-An, additional, Wang, Ting, additional, Hedin, Ulf, additional, Sinha, Sanjay, additional, Barash, Yoseph, additional, Brown, Christopher D., additional, Quertermous, Thomas, additional, and Rader, Daniel J., additional

Published
2020
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14. Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

Author

Kojima, Yoko, Downing, Kelly, Kundu, Ramendra, Miller, Clint, Dewey, Frederick, Lancero, Hope, Raaz, Uwe, Perisic, Ljubica, Hedin, Ulf, Schadt, Eric, Maegdefessel, Lars, Quertermous, Tom, and Leeper, Nicholas J.

Subjects
Health care industry
Abstract

During the assembly of Figure 6A and Supplemental Figure 4C, incorrect flow cytometry plots were included. The authors were able to provide the original data, and a corrected version of [...]

Published
2019
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15. Genetic susceptibility loci for cardiovascular disease and their impact on atherosclerotic plaques

Author

van der Laan, Sander W., Siemelink, Marten A., Haitjema, Saskia, Foroughi Asl, Hassan, Perisic, Ljubica, Mokry, Michal, van Setten, Jessica, Malik, Rainer, Dichgans, Martin, Worrall, Bradford B, Samani, Nilesh J, Schunkert, Heribert, Erdmann, Jeanette, Hedin, Ulf, Paulsson-Berne, Gabrielle, Björkegrenn, Johan L.M, de Borst, Gert J., Asselbergs, Folkert W, den Ruijter, Folkert W, de Bakker, Paul I.W, Pasterkamp, Gerard, Ford, Ian, Sattar, Naveed, and Stott, David J.

Subjects
R1
Abstract

Background:\ud Atherosclerosis is a chronic inflammatory disease in part caused by lipid uptake in the vascular wall, but the exact underlying mechanisms leading to acute myocardial infarction and stroke remain poorly understood. Large consortia identified genetic susceptibility loci that associate with large artery ischemic stroke and coronary artery disease. However, deciphering their underlying mechanisms are challenging. Histological studies identified destabilizing characteristics in human atherosclerotic plaques that associate with clinical outcome. To what extent established susceptibility loci for large artery ischemic stroke and coronary artery disease relate to plaque characteristics is thus far unknown but may point to novel mechanisms.\ud \ud Methods:\ud We studied the associations of 61 established cardiovascular risk loci with 7 histological plaque characteristics assessed in 1443 carotid plaque specimens from the Athero-Express Biobank Study. We also assessed if the genotyped cardiovascular risk loci impact the tissue-specific gene expression in 2 independent biobanks, Biobank of Karolinska Endarterectomy and Stockholm Atherosclerosis Gene Expression.\ud \ud Results:\ud A total of 21 established risk variants (out of 61) nominally associated to a plaque characteristic. One variant (rs12539895, risk allele A) at 7q22 associated to a reduction of intraplaque fat, P=5.09×10−6 after correction for multiple testing. We further characterized this 7q22 Locus and show tissue-specific effects of rs12539895 on HBP1 expression in plaques and COG5 expression in whole blood and provide data from public resources showing an association with decreased LDL (low-density lipoprotein) and increase HDL (high-density lipoprotein) in the blood.\ud \ud Conclusions:\ud Our study supports the view that cardiovascular susceptibility loci may exert their effect by influencing the atherosclerotic plaque characteristics.

Published
2018

17. Genetic Susceptibility Loci for Cardiovascular Disease and Their Impact on Atherosclerotic Plaques

Author

Circulatory Health, Experimentele Afd. Cardiologie 1, CDL Arcadia, MDL onderzoek 1, Onderzoek, Child Health, Device, Onderzoek Precision medicine, Gipskamer Chirurgie, Zorgeenheid Vaatchirurgie Medisch, Brain, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Divisie Biomedische Genetica, CDL Onderzoek Pasterkamp, Divisie LAB, van der Laan, Sander W., Siemelink, Marten A., Haitjema, Saskia, Foroughi Asl, Hassan, Perisic, Ljubica, Mokry, Michal, van Setten, Jessica, Malik, Rainer, Dichgans, Martin, Worrall, Bradford B., Samani, Nilesh J., Schunkert, Heribert, Erdmann, Jeanette, Hedin, Ulf, Paulsson-Berne, Gabrielle, Björkegrenn, Johan L.M., de Borst, Gert J., Asselbergs, Folkert W., den Ruijter, Folkert W., de Bakker, Paul I.W., Pasterkamp, Gerard, METASTROKE Collaboration of the International Stroke Genetics Consortium, Circulatory Health, Experimentele Afd. Cardiologie 1, CDL Arcadia, MDL onderzoek 1, Onderzoek, Child Health, Device, Onderzoek Precision medicine, Gipskamer Chirurgie, Zorgeenheid Vaatchirurgie Medisch, Brain, Cardiovasculaire Epi Team 7a, CMM Groep Kaaij, Divisie Biomedische Genetica, CDL Onderzoek Pasterkamp, Divisie LAB, van der Laan, Sander W., Siemelink, Marten A., Haitjema, Saskia, Foroughi Asl, Hassan, Perisic, Ljubica, Mokry, Michal, van Setten, Jessica, Malik, Rainer, Dichgans, Martin, Worrall, Bradford B., Samani, Nilesh J., Schunkert, Heribert, Erdmann, Jeanette, Hedin, Ulf, Paulsson-Berne, Gabrielle, Björkegrenn, Johan L.M., de Borst, Gert J., Asselbergs, Folkert W., den Ruijter, Folkert W., de Bakker, Paul I.W., Pasterkamp, Gerard, and METASTROKE Collaboration of the International Stroke Genetics Consortium

Published
2018

18. Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling

Author

Hofmann, Patrick, Sommer, Janina, Theodorou, Kosta, Kirchhof, Luisa, Fischer, Ariane, Li, Yuhuang, Perisic, Ljubica, Hedin, Ulf, Mägdefessel, Lars, Dimmeler, Stefanie, Boon, Reinier, Hofmann, Patrick, Sommer, Janina, Theodorou, Kosta, Kirchhof, Luisa, Fischer, Ariane, Li, Yuhuang, Perisic, Ljubica, Hedin, Ulf, Mägdefessel, Lars, Dimmeler, Stefanie, and Boon, Reinier

Abstract

Aims: Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19. Methods and results: H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation. Conclusion: These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.

Published
2018

19. Expression of endothelin type B receptors (EDNRB) on smooth muscle cells is controlled by MKL2, ternary complex factors, and actin dynamics

Author

Krawczyk, Katarzyna K., Skovsted, Gry Freja, Perisic, Ljubica, Dreier, Rasmus, Berg, Jais Oliver, Hedin, Ulf, Rippe, Catarina, Swärd, Karl, Krawczyk, Katarzyna K., Skovsted, Gry Freja, Perisic, Ljubica, Dreier, Rasmus, Berg, Jais Oliver, Hedin, Ulf, Rippe, Catarina, and Swärd, Karl

Abstract

The endothelin type B receptor (ETB or EDNRB) is highly plastic and is upregulated in smooth muscle cells (SMCs) by arterial injury and following organ culture in vitro. We hypothesized that this transcriptional plasticity may arise, in part, because EDNRB is controlled by a balance of transcriptional inputs from myocardin-related transcription factors (MRTFs) and ternary complex factors (TCFs). We found significant positive correlations between the TCFs ELK3 and FLI1 versus EDNRB in human arteries. The MRTF MKL2 also correlated with EDNRB. Overexpression of ELK3, FLI1, and MKL2 in human coronary artery SMCs promoted expression of EDNRB, and the effect of MKL2 was antagonized by myocardin (MYOCD), which also correlated negatively with EDNRB at the tissue level. Silencing of MKL2 reduced basal EDNRB expression, but depolymerization of actin using latrun-culin B (LatB) or overexpression of constitutively active cofilin, as well as treatment with the Rho-associated kinase (ROCK) inhibitor Y27632, increased EDNRB in a MEK/ERK-dependent fashion. Tran-script-specific primers indicated that the second EDNRB transcript (EDNRB_2) was targeted, but this promoter was largely unresponsive to LatB and was inhibited rather than stimulated by MKL2 and FLI1, suggesting distant control elements or an indirect effect. LatB also reduced expression of endothelin-1, but supplementation experiments argued that this was not the cause of EDNRB induction. EDNRB finally changed in parallel with ELK3 and FLI1 in rat and human carotid artery lesions. These studies implicate the actin cytoskeleton and ELK3, FLI1, and MKL2 in the transcriptional control of EDNRB and increase our understanding of the plasticity of this receptor.

Published
2018

23. Therapeutically Targeting the Kinase Activity or Gene Expression of RIP1 Reduces Inflammation-driven Atherosclerosis and Promotes Plaque Stability

Author

Karunakaran, Denuja, primary, Geoffrion, Michele, additional, Wei, Lihui, additional, Gan, Wei, additional, Perisic, Ljubica, additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Sad, Subash, additional, Guo, Liang, additional, Kolodgie, Frank, additional, Ruddy, Terrence, additional, Virmani, Renu, additional, and Rayner, Katey, additional

Published
2018
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25. miRNA Targeting of Oxysterol Binding Protein-like 6 (OSBPL6) Regulates Cholesterol Trafficking and Efflux

Author

Ouimet, Mireille, Hennessy, Elizabeth J., van Solingen, Coen, Koelwyn, Graeme J., Hussein, Maryem A., Ramkhelawon, Bhama, Rayner, Katey J., Temel, Ryan E., Perisic, Ljubica, Hedin, Ulf, Maegdefessel, Lars, Garabedian, Michael J., Holdt, Lesca M., Teupser, Daniel, and Moore, Kathryn J.

Subjects
Male, Receptors, Steroid, Transcription, Genetic, Endoplasmic Reticulum, Transfection, Article, Chlorocebus aethiops, Animals, Humans, 3' Untranslated Regions, Liver X Receptors, Mice, Knockout, Binding Sites, Macrophages, Cholesterol, HDL, Biological Transport, Hep G2 Cells, Atherosclerosis, Plaque, Atherosclerotic, Mice, Inbred C57BL, Disease Models, Animal, MicroRNAs, Cholesterol, HEK293 Cells, Receptors, LDL, Hepatocytes, RNA Interference, ATP Binding Cassette Transporter 1, Protein Binding
Abstract

Cholesterol homeostasis is fundamental to human health and is, thus, tightly regulated. MicroRNAs exert potent effects on biological pathways, including cholesterol metabolism, by repressing genes with related functions. We reasoned that this mode of pathway regulation could be exploited to identify novel genes involved in cholesterol homeostasis.Here, we identify oxysterol-binding protein-like 6 (OSBPL6) as a novel target of 2 miRNA hubs regulating cholesterol homeostasis: miR-33 and miR-27b. Characterization of OSBPL6 revealed that it is transcriptionally regulated in macrophages and hepatocytes by liver X receptor and in response to cholesterol loading and in mice and nonhuman primates by Western diet feeding. OSBPL6 encodes the OSBPL-related protein 6 (ORP6), which contains dual membrane- and endoplasmic reticulum-targeting motifs. Subcellular localization studies showed that ORP6 is associated with the endolysosomal network and endoplasmic reticulum, suggesting a role for ORP6 in cholesterol trafficking between these compartments. Accordingly, knockdown of OSBPL6 results in aberrant clustering of endosomes and promotes the accumulation of free cholesterol in these structures, resulting in reduced cholesterol esterification at the endoplasmic reticulum. Conversely, ORP6 overexpression enhances cholesterol trafficking and efflux in macrophages and hepatocytes. Moreover, we show that hepatic expression of OSBPL6 is positively correlated with plasma levels of high-density lipoprotein cholesterol in a cohort of 200 healthy individuals, whereas its expression is reduced in human atherosclerotic plaques.These studies identify ORP6 as a novel regulator of cholesterol trafficking that is part of the miR-33 and miR-27b target gene networks that contribute to the maintenance of cholesterol homeostasis.

Published
2016

27. Abstract 13: Inhibition of Nudt6 Stabilizes Advanced Atherosclerotic Plaques

Author

Jin, Hong, primary, Li, Yuhuang, additional, Chernogubova, Ekaterina, additional, Bäcklund, Alexandra, additional, Sellberg, Stina, additional, Sun, Changyan, additional, Busch, Albert, additional, Eken, Suzanne M, additional, Perisic, Ljubica, additional, Hedin, Ulf, additional, Tsantilas, Pavlos, additional, Eckstein, Hans-Henning, additional, Pelisek, Jaroslav, additional, and Maegdefessel, Lars, additional

Published
2017
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28. Abstract 95: MiRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

Author

Eken, Suzanne M, primary, Jin, Hong, additional, Chernogubova, Ekaterina, additional, Li, Yuhuang, additional, Simon, Nancy, additional, Sun, Changyan, additional, Korzunowicz, Greg, additional, Busch, Albert, additional, Bäcklund, Alexandra, additional, Österholm, Cecilia, additional, Razuvaev, Anton, additional, Renné, Thomas, additional, Eckstein, Hans H, additional, Pelisek, Jaroslav, additional, Eriksson, Per, additional, Gonzalez Diez, Maria, additional, Matic Perisic, Ljubica, additional, Schellinger, Isabel N, additional, Raaz, Uwe, additional, Leeper, Nicholas J, additional, Hansson, Göran K, additional, Paulsson-Berne, Gabrielle, additional, Hedin, Ulf, additional, and Maegdefessel, Lars, additional

Published
2017
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29. Abstract 219: Deficiency of the T Cell Regulator Cbl-B Aggravates Atherosclerosis by Inducing CD8 + T Cell-Mediated Macrophage Death

Author

Seijkens, Tom T, primary, Winkels, Holger, additional, Gijbels, Marion, additional, Kuivenhoven, Jan A, additional, Perisic, Ljubica, additional, Paulsson-Berne, Gabrielle, additional, Hedin, Ulf, additional, Hansson, Goran K, additional, Weber, Christian, additional, Gerdes, Norbert, additional, de Winther, Menno P, additional, and Lutgens, Esther, additional

Published
2017
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30. Therapeutically inhibiting macrophage necroptosis reduces inflammation‐driven atherosclerosis and promotes plaque stability

Author

Karunakaran, Denuja, primary, Geoffrion, Michele, additional, Lee, Richard, additional, Wei, Lihui, additional, Gan, Wei, additional, Perisic, Ljubica, additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Sad, Subash, additional, Guo, Liang, additional, Kolodgie, Frank, additional, Ruddy, Terrence, additional, Virmani, Renu, additional, and Rayner, Katey, additional

Published
2017
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32. Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling.

Author

Hofmann, Patrick, Sommer, Janina, Theodorou, Kosta, Kirchhof, Luisa, Fischer, Ariane, Li, Yuhuang, Perisic, Ljubica, Hedin, Ulf, Maegdefessel, Lars, Dimmeler, Stefanie, and Boon, Reinier A

Abstract

Aims Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19. Methods and results H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation. Conclusion These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

Author

Karadimou, Glykeria, Folkersen, Lasse, Berg, Martin, Perisic, Ljubica, Discacciati, Andrea, Roy, Joy, Hansson, Göran K, Persson, Jonas, Paulsson-Berne, Gabrielle, Karadimou, Glykeria, Folkersen, Lasse, Berg, Martin, Perisic, Ljubica, Discacciati, Andrea, Roy, Joy, Hansson, Göran K, Persson, Jonas, and Paulsson-Berne, Gabrielle

Abstract

Aims: Processes in the development of atherosclerotic lesions can lead to plaque rupture or erosion, which can in turn elicit myocardial infarction or ischaemic stroke. The aims of this study were to determine whether Toll-like receptor 7 (TLR7) gene expression levels influence patient outcome and to explore the mechanisms linked to TLR7 expression in atherosclerosis. Methods and Results: Atherosclerotic plaques were removed by carotid endarterectomy (CEA) and subjected to gene array expression analysis (n=123). Increased levels of TLR7 transcript in the plaques were associated with better outcome in a follow-up study over a maximum of 8 years. Patients with higher TLR7 transcript levels had a lower risk of experiencing major cardiovascular and cerebrovascular events (MACCE) during the follow-up period after CEA (hazard ratio: 2.38, p=0.012, 95% CI 1.21-4.67). TLR7 was expressed in all plaques by T cells, macrophages and endothelial cells in capillaries, as shown by immunohistochemistry. In short-term tissue cultures, ex vivo treatment of plaques with the TLR7 ligand imiquimod elicited dose-dependent secretion of IL-10, TNF-α, GM-CSF, and IL-12/IL-23p40. This secretion was blocked with a TLR7 inhibitor. Immunofluorescent tissue analysis after TLR7 stimulation showed IL-10 expression in T cells, macrophages and vascular smooth muscle cells. TLR7 mRNA levels in the plaques were correlated with IL-10 receptor (r=0.4031, p<0.0001) and GM-CSF receptor A (r=0.4354, p<0.0001) transcripts.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Conclusions These findings demonstrate that TLR7 is abundantly expressed in human atherosclerotic plaques. TLR7 ligation eli

Published
2016

34. Functional Analysis of a Novel Genome-Wide Association Study Signal in SMAD3 That Confers Protection From Coronary Artery Disease

Author

Turner, Adam W., Martinuk, Amy, Silva, Anada, Lau, Paulina, Nikpay, Majid, Eriksson, Per, Folkersen, Lasse, Perisic, Ljubica, Hedin, Ulf, Soubeyrand, Sebastien, McPherson, Ruth, Turner, Adam W., Martinuk, Amy, Silva, Anada, Lau, Paulina, Nikpay, Majid, Eriksson, Per, Folkersen, Lasse, Perisic, Ljubica, Hedin, Ulf, Soubeyrand, Sebastien, and McPherson, Ruth

Abstract

OBJECTIVE—: A recent genome-wide association study meta-analysis identified an intronic single nucleotide polymorphism in SMAD3, rs56062135C>T, the minor allele (T) which associates with protection from coronary artery disease. Relevant to atherosclerosis, SMAD3 is a key contributor to transforming growth factor-β pathway signaling. Here, we seek to identify ≥1 causal coronary artery disease–associated single nucleotide polymorphisms at the SMAD3 locus and characterize mechanisms whereby the risk allele(s) contribute to coronary artery disease risk. APPROACH AND RESULTS—: By genetic and epigenetic fine mapping, we identified a candidate causal single nucleotide polymorphism rs17293632C>T (D′, 0.97; r, 0.94 with rs56062135) in intron 1 of SMAD3 with predicted functional effects. We show that the sequence encompassing rs17293632 acts as a strong enhancer in human arterial smooth muscle cells. The common allele (C) preserves an activator protein (AP)-1 site and enhancer function, whereas the protective (T) allele disrupts the AP-1 site and significantly reduces enhancer activity (PT single nucleotide polymorphism represents a novel functional cis-acting element at the SMAD3 locus. The protective (T) allele of rs17293632 disrupts a consensus AP-1 binding site in a SMAD3 intron 1 enhancer, reduces enhancer activity and SMAD3 expression, altering human arterial smooth muscle cells proliferation.

Published
2016

35. Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci

Author

Miller, Clint L., Pjanic, Milos, Wang, Ting, Nguyen, Trieu, Cohain, Ariella, Lee, Jonathan D., Perisic, Ljubica, Hedin, Ulf, Kundu, Ramendra K., Majmudar, Deshna, Kim, Juyong B., Wang, Oliver, Betsholtz, Christer, Ruusalepp, Arno, Franzen, Oscar, Assimes, Themistocles L., Montgomery, Stephen B., Schadt, Eric E., Bjorkegren, Johan L. M., Quertermous, Thomas, Miller, Clint L., Pjanic, Milos, Wang, Ting, Nguyen, Trieu, Cohain, Ariella, Lee, Jonathan D., Perisic, Ljubica, Hedin, Ulf, Kundu, Ramendra K., Majmudar, Deshna, Kim, Juyong B., Wang, Oliver, Betsholtz, Christer, Ruusalepp, Arno, Franzen, Oscar, Assimes, Themistocles L., Montgomery, Stephen B., Schadt, Eric E., Bjorkegren, Johan L. M., and Quertermous, Thomas

Abstract

Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified 4150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.

Published
2016
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36. Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci

Author

Miller, Clint L., primary, Pjanic, Milos, additional, Wang, Ting, additional, Nguyen, Trieu, additional, Cohain, Ariella, additional, Lee, Jonathan D., additional, Perisic, Ljubica, additional, Hedin, Ulf, additional, Kundu, Ramendra K., additional, Majmudar, Deshna, additional, Kim, Juyong B., additional, Wang, Oliver, additional, Betsholtz, Christer, additional, Ruusalepp, Arno, additional, Franzén, Oscar, additional, Assimes, Themistocles L., additional, Montgomery, Stephen B., additional, Schadt, Eric E., additional, Björkegren, Johan L.M., additional, and Quertermous, Thomas, additional

Published
2016
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37. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis

Author

Karunakaran, Denuja, primary, Geoffrion, Michele, additional, Wei, Lihui, additional, Gan, Wei, additional, Richards, Laura, additional, Shangari, Prakriti, additional, DeKemp, Ella M., additional, Beanlands, Rachelle A., additional, Perisic, Ljubica, additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Sad, Subash, additional, Guo, Liang, additional, Kolodgie, Frank D., additional, Virmani, Renu, additional, Ruddy, Terrence, additional, and Rayner, Katey J., additional

Published
2016
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38. Abstract 173: Proprotein Convertase Subtilisin/Kexin Type 6 is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Disease

Author

Hedin, Ulf, primary, Perisic, Ljubica, additional, Rykaczewska, Urszula, additional, Razuvaev, Anton, additional, Lengquist, Mariette, additional, Sabater-Lleal, Maria, additional, Eriksson, Ida, additional, Röhl, Samuel, additional, Kronqvist, Malin, additional, Tseng, Chi-Nan, additional, Rodriguez, Patricia, additional, Folkersen, Lasse, additional, Du, Lei, additional, Gonzalez Diez, Maria, additional, Osterholm, Cecilia, additional, Roy, Joy, additional, Patrakka, Jaakko, additional, Paulsson-Berne, Gabrielle, additional, Hansson, Göran, additional, Odeberg, Jacob, additional, Hamsten, Anders, additional, and Eriksson, Per, additional

Published
2016
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39. Abstract 3: Targeting Macrophage Necroptosis for Therapeutic and Diagnostic Interventions to Treat Atherosclerosis

Author

Karunakaran, Denuja, primary, Geoffrion, Michele, additional, Wei, Lihui, additional, Gan, Wei, additional, Perisic, Ljubica, additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Sad, Subash, additional, Ruddy, Terrence, additional, Guo, Liang, additional, Kolodgie, Frank, additional, Virmani, Renu, additional, and Rayner, Katey J, additional

Published
2016
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40. Abstract 19: Role of Adenosine-to-Inosine RNA Editing of Alu Elements in Human Vascular Inflammatory Diseases

Author

Stellos, Konstantinos, primary, Gatsiou, Aikaterini, additional, Stamatelopoulos, Kimon, additional, Perisic, Ljubica, additional, John, David, additional, Lunella, Federica F, additional, Jae, Nicolas, additional, Rossbach, Oliver, additional, Amrhein, Carolin, additional, Sigala, Frangiska, additional, Boon, Reinier A, additional, Fuertig, Boris, additional, Manavski, Yosif, additional, You, Xintian, additional, Uchida, Shizuka, additional, Keller, Till, additional, Boeckel, Jes-Niels, additional, Franco-Cereceda, Anders, additional, Maegdefessel, Lars, additional, Chen, Wei, additional, Schwalbe, Harald, additional, Bindereif, Albrecht, additional, Eriksson, Per, additional, Hedin, Ulf, additional, Zeiher, Andreas M, additional, and Dimmeler, Stefanie, additional

Published
2016
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41. miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux

Author

Ouimet, Mireille, primary, Hennessy, Elizabeth J., additional, van Solingen, Coen, additional, Koelwyn, Graeme J., additional, Hussein, Maryem A., additional, Ramkhelawon, Bhama, additional, Rayner, Katey J., additional, Temel, Ryan E., additional, Perisic, Ljubica, additional, Hedin, Ulf, additional, Maegdefessel, Lars, additional, Garabedian, Michael J., additional, Holdt, Lesca M., additional, Teupser, Daniel, additional, and Moore, Kathryn J., additional

Published
2016
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42. Abstract 512: The Long Non-coding Rna MIAT Regulates Smooth Muscle Cell Proliferation and Macrophage Activity in Advanced Atherosclerotic Lesions

Author

Li, Yuhuang, primary, Jin, Hong, additional, Perisic, Ljubica, additional, Chernogubova, Ekaterina, additional, Bäcklund, Alexandra, additional, Gustafsson, Peter, additional, Werngren, Olivera, additional, Busch, Albert, additional, Eken, Suzanne, additional, Sun, Changyan, additional, Hansson, Göran K, additional, Paulsson-Berne, Gabrielle, additional, Hedin, Ulf, additional, Bergmark, Claes, additional, and Maegdefessel, Lars, additional

Published
2016
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43. Abstract 127: Induction of miR-21 Increases Fibrous Cap Stability in Vulnerable Atherosclerotic Lesions

Author

Jin, Hong, primary, Li, Yuhuang, additional, Bäcklund, Alexandra, additional, Busch, Albert, additional, Eken, Suzanne M, additional, Chernogubova, Ekaterina, additional, Gustafsson, Peter, additional, Perisic, Ljubica, additional, Schellinger, Isabel, additional, Raaz, Uwe, additional, Tsao, Philip S, additional, Hansson, Göran K, additional, Paulsson- Berne, Gabrielle, additional, Hedin, Ulf, additional, and Maegdefessel, Lars, additional

Published
2016
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46. CDKN2B Regulates TGF β Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels

Author

Nanda, Vivek, primary, Downing, Kelly P., additional, Ye, Jianqin, additional, Xiao, Sophia, additional, Kojima, Yoko, additional, Spin, Joshua M., additional, DiRenzo, Daniel, additional, Nead, Kevin T., additional, Connolly, Andrew J., additional, Dandona, Sonny, additional, Perisic, Ljubica, additional, Hedin, Ulf, additional, Maegdefessel, Lars, additional, Dalman, Jessie, additional, Guo, Liang, additional, Zhao, XiaoQing, additional, Kolodgie, Frank D., additional, Virmani, Renu, additional, Davis, Harry R., additional, and Leeper, Nicholas J., additional

Published
2016
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47. Schip1 Is a Novel Podocyte Foot Process Protein that Mediates Actin Cytoskeleton Rearrangements and Forms a Complex with Nherf2 and Ezrin

Author

Perisic, Ljubica, Rodriguez, Patricia Q., Hultenby, Kjell, Sun, Ying, Lal, Mark, Betsholtz, Christer, Uhlén, Mathias, Wernerson, Annika, Hedin, Ulf, Pikkarainen, Timo, Tryggvason, Karl, Patrakka, Jaakko, Perisic, Ljubica, Rodriguez, Patricia Q., Hultenby, Kjell, Sun, Ying, Lal, Mark, Betsholtz, Christer, Uhlén, Mathias, Wernerson, Annika, Hedin, Ulf, Pikkarainen, Timo, Tryggvason, Karl, and Patrakka, Jaakko

Abstract

Background Podocyte foot process effacement accompanied by actin cytoskeleton rearrangements is a cardinal feature of many progressive human proteinuric diseases. Results By microarray profiling of mouse glomerulus, SCHIP1 emerged as one of the most highly enriched transcripts. We detected Schip1 protein in the kidney glomerulus, specifically in podocytes foot processes. Functionally, Schip1 inactivation in zebrafish by morpholino knock-down results in foot process disorganization and podocyte loss leading to proteinuria. In cultured podocytes Schip1 localizes to cortical actin-rich regions of lamellipodia, where it forms a complex with Nherf2 and ezrin, proteins known to participate in actin remodeling stimulated by PDGF beta signaling. Mechanistically, overexpression of Schip1 in vitro causes accumulation of cortical F-actin with dissolution of transversal stress fibers and promotes cell migration in response to PDGF-BB stimulation. Upon actin disassembly by latrunculin A treatment, Schip1 remains associated with the residual F-actin-containing structures, suggesting a functional connection with actin cytoskeleton possibly via its interaction partners. A similar assay with cytochalasin D points to stabilization of cortical actin cytoskeleton in Schip1 overexpressing cells by attenuation of actin depolymerisation. Conclusions Schip1 is a novel glomerular protein predominantly expressed in podocytes, necessary for the zebrafish pronephros development and function. Schip1 associates with the cortical actin cytoskeleton network and modulates its dynamics in response to PDGF signaling via interaction with the Nherf2/ezrin complex. Its implication in proteinuric diseases remains to be further investigated., QC 20150513

Published
2015
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48. Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis

Author

Karunakaran, Denuja, primary, Thrush, A. Brianne, additional, Nguyen, My-Anh, additional, Richards, Laura, additional, Geoffrion, Michele, additional, Singaravelu, Ragunath, additional, Ramphos, Eleni, additional, Shangari, Prakriti, additional, Ouimet, Mireille, additional, Pezacki, John P., additional, Moore, Kathryn J., additional, Perisic, Ljubica, additional, Maegdefessel, Lars, additional, Hedin, Ulf, additional, Harper, Mary-Ellen, additional, and Rayner, Katey J., additional

Published
2015
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49. Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap

Author

Nurnberg, Sylvia T., primary, Cheng, Karen, additional, Raiesdana, Azad, additional, Kundu, Ramendra, additional, Miller, Clint L., additional, Kim, Juyong B., additional, Arora, Komal, additional, Carcamo-Oribe, Ivan, additional, Xiong, Yiqin, additional, Tellakula, Nikhil, additional, Nanda, Vivek, additional, Murthy, Nikitha, additional, Boisvert, William A., additional, Hedin, Ulf, additional, Perisic, Ljubica, additional, Aldi, Silvia, additional, Maegdefessel, Lars, additional, Pjanic, Milos, additional, Owens, Gary K., additional, Tallquist, Michelle D., additional, and Quertermous, Thomas, additional

Published
2015
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50. Correction: Schip1 Is a Novel Podocyte Foot Process Protein that Mediates Actin Cytoskeleton Rearrangements and Forms a Complex with Nherf2 and Ezrin

Author

Perisic, Ljubica, primary, Rodriguez, Patricia Q., additional, Hultenby, Kjell, additional, Sun, Ying, additional, Lal, Mark, additional, Betsholtz, Christer, additional, Uhlén, Mathias, additional, Wernerson, Annika, additional, Hedin, Ulf, additional, Pikkarainen, Timo, additional, Tryggvason, Karl, additional, and Patrakka, Jaakko, additional

Published
2015
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