WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function

Anne-Mari Moilanen; Jaana Rysä; Leena Kaikkonen; Teemu Karvonen; Erja Mustonen; Raisa Serpi; Zoltán Szabó; Olli Tenhunen; Zsolt Bagyura; Juha Näpänkangas; Pauli Ohukainen; Pasi Tavi; Risto Kerkelä; Margrét Leósdóttir; Björn Wahlstrand; Thomas Hedner; Olle Melander; Heikki Ruskoaho

doi:10.1371/journal.pone.0124907

WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function

PLoS One. 2015 Apr 27;10(4):e0124907. doi: 10.1371/journal.pone.0124907. eCollection 2015.

Authors

Anne-Mari Moilanen¹, Jaana Rysä², Leena Kaikkonen², Teemu Karvonen², Erja Mustonen², Raisa Serpi³, Zoltán Szabó², Olli Tenhunen², Zsolt Bagyura⁴, Juha Näpänkangas⁵, Pauli Ohukainen², Pasi Tavi⁶, Risto Kerkelä⁷, Margrét Leósdóttir⁸, Björn Wahlstrand⁹, Thomas Hedner⁹, Olle Melander¹⁰, Heikki Ruskoaho¹¹

Affiliations

¹ The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Department of Pathology, The Institute of Diagnostics, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
² The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
³ The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
⁴ Heart Center, Semmelweis University, Budapest, Hungary.
⁵ Department of Pathology, The Institute of Diagnostics, University of Oulu, Oulu, Finland.
⁶ Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
⁷ The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
⁸ Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Cardiology, Skåne University Hospital, Malmö, Sweden.
⁹ Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁰ Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
¹¹ The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Animals
Cell Cycle Proteins
Cells, Cultured
Female
HSP27 Heat-Shock Proteins / genetics
HSP27 Heat-Shock Proteins / metabolism
Heart Failure / genetics
Heart Failure / metabolism*
Heart Failure / physiopathology
Hemodynamics*
Humans
Male
Middle Aged
Myocardial Infarction / genetics
Myocardial Infarction / metabolism*
Myocardial Infarction / physiopathology
Myocytes, Cardiac / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
RNA-Binding Proteins
Rats
Rats, Sprague-Dawley
Up-Regulation*
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

Cell Cycle Proteins
HSP27 Heat-Shock Proteins
Nuclear Proteins
RNA-Binding Proteins
WDR12 protein, human
p38 Mitogen-Activated Protein Kinases

Grants and funding

This work was supported by the Academy of Finland (Center of Excellence) (HR), Academy of Finland (JR), Sigrid Juselius Foundation (HR), Finnish Foundation for Cardiovascular Research (HR, JR and RS), the National Technology Foundation TEKES (HR), Biocenter Finland (HR and RS) and European Research Council StG-282255 (OM), the Swedish Medical Research Council (OM), the Swedish Heart and Lung Foundation (OM), the Novo Nordisk Foundation (OM) and LUA/ALF – ALFGBG151121 (TH and BW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.