WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function
In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of...
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| Published in | PloS one Vol. 10; no. 4; p. e0124907 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
27.04.2015
Public Library of Science (PLoS) |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1932-6203 1932-6203 |
| DOI | 10.1371/journal.pone.0124907 |
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| Abstract | In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown.
We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size.
WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. |
|---|---|
| AbstractList | Aims In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. Methods and Results We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen–activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. Conclusions WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. Aims In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. Methods and Results We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen–activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. Conclusions WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. Aims In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of WDR12 in the heart is unknown. We characterized cardiac expression of WDR12, used adenovirus-mediated WDR12 gene delivery to examine effects of WDR12 on left ventricular (LV) remodeling, and analyzed relationship between MI associated WDR12 allele and cardiac function in human subjects. LV WDR12 protein levels were increased in patients with dilated cardiomyopathy and rats post-infarction. In normal adult rat hearts, WDR12 gene delivery into the anterior wall of the LV decreased interventricular septum diastolic and systolic thickness and increased the diastolic and systolic diameters of the LV. Moreover, LV ejection fraction (9.1%, P<0.05) and fractional shortening (12.2%, P<0.05) were declined. The adverse effects of WDR12 gene delivery on cardiac function were associated with decreased cellular proliferation, activation of p38 mitogen-activated protein kinase (MAPK)/heat shock protein (HSP) 27 pathway, and increased protein levels of Block of proliferation 1 (BOP1), essential for ribosome biogenesis. Post-infarction WDR12 gene delivery decreased E/A ratio (32%, P<0.05) suggesting worsening of diastolic function. In human subjects, MI associated WDR12 allele was associated significantly with diastolic dysfunction and left atrial size. WDR12 triggers distinct deterioration of cardiac function in adult rat heart and the MI associated WDR12 variant is associated with diastolic dysfunction in human subjects. |
| Audience | Academic |
| Author | Hedner, Thomas Karvonen, Teemu Tavi, Pasi Leósdóttir, Margrét Mustonen, Erja Serpi, Raisa Näpänkangas, Juha Ruskoaho, Heikki Bagyura, Zsolt Kaikkonen, Leena Tenhunen, Olli Moilanen, Anne-Mari Szabó, Zoltán Wahlstrand, Björn Ohukainen, Pauli Kerkelä, Risto Rysä, Jaana Melander, Olle |
| AuthorAffiliation | University of Tampere, FINLAND 2 Department of Pathology, The Institute of Diagnostics, University of Oulu, Oulu, Finland 3 Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland 7 Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 8 Department of Clinical Sciences, Lund University, Lund, Sweden 11 Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland 6 Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland 9 Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden 5 Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland 1 The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland 4 Heart Center, Semmelweis University, Budapest, Hungary 10 Department of Cardiology, Skåne University Hospi |
| AuthorAffiliation_xml | – name: 7 Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden – name: 9 Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden – name: 11 Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland – name: 3 Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland – name: 10 Department of Cardiology, Skåne University Hospital, Malmö, Sweden – name: 2 Department of Pathology, The Institute of Diagnostics, University of Oulu, Oulu, Finland – name: 5 Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland – name: 8 Department of Clinical Sciences, Lund University, Lund, Sweden – name: 6 Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland – name: 1 The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland – name: 4 Heart Center, Semmelweis University, Budapest, Hungary – name: University of Tampere, FINLAND |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25915632$$D View this record in MEDLINE/PubMed https://gup.ub.gu.se/publication/218017$$DView record from Swedish Publication Index |
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| CitedBy_id | crossref_primary_10_3389_fgene_2022_1008502 crossref_primary_10_1074_jbc_M115_693259 crossref_primary_10_1002_jcp_29635 crossref_primary_10_1080_08037051_2016_1273741 crossref_primary_10_1038_s41598_018_23042_w crossref_primary_10_1111_bcpt_13398 |
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| Copyright | COPYRIGHT 2015 Public Library of Science 2015 Moilanen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2015 Moilanen et al 2015 Moilanen et al |
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| CorporateAuthor | Lunds universitet Profile areas and other strong research environments Department of Clinical Sciences, Malmö Lund University Kardiovaskulär forskning - hypertoni Strategiska forskningsområden (SFO) EpiHealth: Epidemiology for Health EXODIAB: Excellence of Diabetes Research in Sweden Faculty of Medicine Internmedicin - epidemiologi Strategic research areas (SRA) Medicinska fakulteten Profilområden och andra starka forskningsmiljöer Internal Medicine - Epidemiology Institutionen för kliniska vetenskaper, Malmö Cardiovascular Research - Hypertension |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 Conceived and designed the experiments: AMM JR OM HR. Performed the experiments: AMM JR LK TK EM RS ZS OT ZB PT. Analyzed the data: AMM JR LK EM RS ZS OT ZB JN PO PT RK ML BW OM. Contributed reagents/materials/analysis tools: RK ML BW TH OM HR. Wrote the paper: AMM JR TH OM HR. Competing Interests: The authors have declared that no competing interests exist. |
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| Snippet | In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function of... Aims In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function... Aims In a recent genome-wide association study, WD-repeat domain 12 (WDR12) was associated with early-onset myocardial infarction (MI). However, the function... |
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| SubjectTerms | ACTIVATED PROTEIN-KINASE Adenoviruses Adult Age Alleles Animals Annan klinisk medicin Apoptosis BIOGENESIS Biosynthesis Cardiology and Cardiovascular Disease Cardiomyopathy Cells, Cultured Clinical Medicine Deterioration Dilated cardiomyopathy Female Gene expression Gene transfer Genome-wide association studies Genomes Genomics Heart Heart attack Heart diseases Heart Failure - genetics Heart Failure - metabolism Heart Failure - physiopathology Heat shock Heat shock proteins Hemodynamics HSP27 Heat-Shock Proteins - genetics HSP27 Heat-Shock Proteins - metabolism Humans HYPERTENSION II-INDUCED IMMUNE-RESPONSES IN-VIVO Infarction Kardiologi och kardiovaskulära sjukdomar Klinisk medicin Male MAP kinase Medical and Health Sciences Medicin och hälsovetenskap Middle Aged Multidisciplinary Sciences Myocardial Infarction - genetics Myocardial Infarction - metabolism Myocardial Infarction - physiopathology MYOCARDIAL-INFARCTION Myocytes, Cardiac - metabolism NATRIURETIC-PEPTIDE Nuclear Proteins - genetics Nuclear Proteins - metabolism Nucleoli Other Clinical Medicine p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism PEPTIDE GENE-EXPRESSION Protein kinase Rats Rats, Sprague-Dawley RIBOSOME Septum SOCIETY-OF-CARDIOLOGY Up-Regulation Ventricle WD-REPEAT |
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| Title | WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/25915632 https://www.proquest.com/docview/1676152241 https://pubmed.ncbi.nlm.nih.gov/PMC4411154 https://gup.ub.gu.se/publication/218017 https://doaj.org/article/e416c35c82ba453588bc9aff56ae1b0b http://dx.doi.org/10.1371/journal.pone.0124907 |
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