| 1. |
- Celik, Selvi, et al.
(författare)
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Antisense regulation of atrial natriuretic peptide expression
- 2019
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 4:19
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Tidskriftsartikel (refereegranskat)abstract
- The cardiac hormone atrial natriuretic peptide (ANP) is a central regulator of blood volume and a therapeutic target in hypertension and heart failure. Enhanced ANP activity in such conditions through inhibition of the degradative enzyme neprilysin has shown clinical efficacy but is complicated by consequences of simultaneous accumulation of a heterogeneous array of other hormones. Targets for specific ANP enhancement have not been available. Here, we describe a cis-acting antisense transcript (NPPA-AS1), which negatively regulates ANP expression in human cardiomyocytes. We show that NPPA-AS1 regulates ANP expression via facilitating NPPA repressor RE1-silencing transcription factor (REST) binding to its promoter, rather than forming an RNA duplex with ANP mRNA. Expression of ANP mRNA and NPPA-AS1 was increased and correlated in isolated strained human cardiomyocytes and in hearts from patients with advanced heart failure. Further, inhibition of NPPA-AS1 in vitro and in vivo resulted in increased myocardial expression of ANP, increased circulating ANP, increased renal cGMP, and lower blood pressure. The effects of NPPA-AS1 inhibition on NPPA expression in human cardiomyocytes were further marked under cell-strain conditions. Collectively, these results implicate the antisense transcript NPPA-AS1 as part of a physiologic self-regulatory ANP circuit and a viable target for specific ANP augmentation.
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| 2. |
- Celik, Selvi, et al.
(författare)
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Extracellular Vesicle-Associated TWEAK Contributes to Vascular Inflammation and Remodeling During Acute Cellular Rejection
- 2023
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Ingår i: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 8:5, s. 439-456
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Tidskriftsartikel (refereegranskat)abstract
- Acute cellular rejection (ACR) is a leading cause of graft loss and death after heart transplantation despite effective immunosuppressive therapies. The identification of factors that impair graft vascular barrier function or promote immune cell recruitment during ACR could provide new therapeutic opportunities for the treatment of patients who receive transplants. In 2 ACR cohorts, we found the extracellular vesicle-associated cytokine TWEAK to be elevated during ACR. Vesicular TWEAK promoted expression of proinflammatory genes and the release of chemoattractant cytokines from human cardiac endothelial cells. We conclude that vesicular TWEAK is a novel target with potential therapeutic implications in ACR.
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| 3. |
- Celik, Selvi, et al.
(författare)
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Functional Screening Identifies MicroRNA Regulators of Corin Activity and Atrial Natriuretic Peptide Biogenesis
- 2019
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Ingår i: Molecular and Cellular Biology. - 0270-7306. ; 39:23
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Tidskriftsartikel (refereegranskat)abstract
- Atrial natriuretic peptide (ANP) represents an attractive therapeutic target in hypertension and heart failure. The biologically active form of ANP is produced by the cardiac serine protease corin, and modulation of its activity might therefore represent a novel approach for ANP augmentation. MicroRNAs (miRNAs) are pervasive regulators of gene expression, but their potential role in regulating corin activity has not been elucidated. Our aim was to systematically identify and characterize miRNA regulators of corin activity in human cardiomyocytes. An assay for measuring serine protease activity in human induced pluripotent stem cell (iPS)-derived cardiomyocytes was used to perform a comprehensive screening of miRNA family inhibitors (n = 42). miRNA 1-3p (miR-1-3p) was identified as a potent inhibitor of corin activity. The interaction between miR-1-3p and a specific target site in the CORIN 3' untranslated region (3' UTR) was confirmed through argonaute 2 (AGO2)-RNA immunoprecipitation and reporter assays. Inhibition of miR-1-3p resulted in upregulation of CORIN gene and protein expression, as well as a concomitant increase in extracellular ANP. Additionally, miR-1-3p was found to interact with and inhibit the expression of several transcriptional activators of ANP gene expression. In conclusion, we have identified a novel regulator of corin activity and ANP biogenesis in human cardiomyocytes that might be of potential future therapeutic utility.
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| 4. |
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| 5. |
- Egerstedt, Anna, et al.
(författare)
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Profiling of the plasma proteome across different stages of human heart failure
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 5830-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.
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| 6. |
- Gidlöf, Olof, et al.
(författare)
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Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing
- 2020
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- While restoration of coronary blood flow to the ischemic heart is the most effective strategy for reducing infarct size, reperfusion injury represents a significant limiting factor on clinical outcomes in myocardial infarction patients. Ischemic preconditioning (IPC) has been shown to inhibit reperfusion injury and represents an attractive model for studying cardioprotective signal transduction pathways. Long non-coding RNAs (lncRNAs) are a structurally and functionally heterogenous class of RNA transcripts with unknown roles in IPC-induced cardioprotection. Through microarray-based expression profiling of 31,423 lncRNAs in cardiac tissue from IPC mice, we identified the nuclear transcript Neat1 to be rapidly and robustly decreased in response to IPC. siRNA-mediated knock down of Neat1 reduced apoptosis and necrosis in murine cardiomyocytes (CM) and human iPS-derived CMs in response to prolonged hypoxia and hypoxia-reoxygenation, assessed with Annexin V/propidium iodide-staining, a Caspase 3/7 activity assay, LDH release, and western blot for cleaved Caspase 3. Mechanistically, Neat1 was shown to regulate processing of pro-apoptotic microRNA-22 (miR-22) in murine and human CM nuclei using a luciferase reporter assay. Hypoxia-induced downregulation of Neat1 was shown to result in accumulation of unprocessed pri-miRNA and decreased availability of biologically active miRNA, including miR-22. Addition of exogenous synthetic miR-22 reversed the protective effect of Neat1 knock down in human iPS-CM. In conclusion, we have identified the nuclear lncRNA Neat1 as part of a conserved oxygen-sensitive feedback mechanism by regulation of miRNA processing and a potential target in cardioprotection.
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| 7. |
- Gidlöf, Olof, et al.
(författare)
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Ischemic Preconditioning Confers Epigenetic Repression of Mtor and Induction of Autophagy Through G9a-Dependent H3K9 Dimethylation
- 2016
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Ischemic preconditioning (IPC) protects the heart from prolonged ischemic insult and reperfusion injury through a poorly understood mechanism. Post-translational modifications of histone residues can confer rapid and drastic switches in gene expression in response to various stimuli, including ischemia. The aim of this study was to investigate the effect of histone methylation in the response to cardiac ischemic preconditioning.METHODS AND RESULTS: We used cardiac biopsies from mice subjected to IPC to quantify global levels of 3 of the most well-studied histone methylation marks (H3K9me2, H3K27me3, and H3K4me3) with Western blot and found that H3K9me2 levels were significantly increased in the area at risk compared to remote myocardium. In order to assess which genes were affected by the increase in H3K9me2 levels, we performed ChIP-Seq and transcriptome profiling using microarray. Two hundred thirty-seven genes were both transcriptionally repressed and enriched in H3K9me2 in the area at risk of IPC mice. Of these, Mtor (Mechanistic target of rapamycin) was chosen for mechanistic studies. Knockdown of the major H3K9 methyltransferase G9a resulted in a significant decrease in H3K9me2 levels across Mtor, increased Mtor expression, as well as decreased autophagic activity in response to rapamycin and serum starvation.CONCLUSIONS: IPC confers an increase of H3K9me2 levels throughout the Mtor gene-a master regulator of cellular metabolism and a key player in the cardioprotective effect of IPC-leading to transcriptional repression via the methyltransferase G9a. The results of this study indicate that G9a has an important role in regulating cardiac autophagy and the cardioprotective effect of IPC.
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| 8. |
- Knutsson, Anki, et al.
(författare)
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Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE-/- mice
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE-/- mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0-3.1), 0.2% (IQR 0-4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.
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| 9. |
- Martínez, Marycarmen Arévalo, et al.
(författare)
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Vascular smooth muscle–specific YAP/TAZ deletion triggers aneurysm development in mouse aorta
- 2023
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Ingår i: JCI Insight. - 2379-3708. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- Inadequate adaption to mechanical forces, including blood pressure, contributes to development of arterial aneurysms. Recent studies have pointed to a mechanoprotective role of YAP and TAZ in vascular smooth muscle cells (SMCs). Here, we identified reduced expression of YAP1 in human aortic aneurysms. Vascular SMC–specific knockouts (KOs) of YAP/TAZ were thus generated using the integrin α8–Cre (Itga8-Cre) mouse model (i8-YT-KO). i8-YT-KO mice spontaneously developed aneurysms in the abdominal aorta within 2 weeks of KO induction and in smaller arteries at later times. The vascular specificity of Itga8-Cre circumvented gastrointestinal effects. Aortic aneurysms were characterized by elastin disarray, SMC apoptosis, and accumulation of proteoglycans and immune cell populations. RNA sequencing, proteomics, and myography demonstrated decreased contractile differentiation of SMCs and impaired vascular contractility. This associated with partial loss of myocardin expression, reduced blood pressure, and edema. Mediators in the inflammatory cGAS/STING pathway were increased. A sizeable increase in SOX9, along with several direct target genes, including aggrecan (Acan), contributed to proteoglycan accumulation. This was the earliest detectable change, occurring 3 days after KO induction and before the proinflammatory transition. In conclusion, Itga8-Cre deletion of YAP and TAZ represents a rapid and spontaneous aneurysm model that recapitulates features of human abdominal aortic aneurysms.
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| 10. |
- Pimpalwar, Neha, et al.
(författare)
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Analysis of genetic variant associated with heart failure mortality implicates thymic stromal lymphopoietin as mediator of strain-induced myocardial fibroblast-mast cell crosstalk and fibrosis
- 2024
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Ingår i: FASEB JOURNAL. - 0892-6638 .- 1530-6860. ; 38:4
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome-wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix-loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor beta expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow-up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling. The extent and patterning of myocardial fibrosis are important determinants of outcome in heart disease. Here, we report that increased strain in myocardial cells results in increased expression of thymic stromal lymphopoietin (TSLP). Furthermore, increased TSLP expression, modulated by the transcription factor nescient helix-loop helix 1 (NHLH1), induces increased transforming growth factor beta (TGF-beta) expression in myocardial mast cells and tissue fibrosis. Our findings thus implicate a novel pathway in myocardial tissue homeostasis and putative therapeutic target to prevent fibrosis.image
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