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


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.
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.
Anne-Mari
AM
Moilanen
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Jaana
J
Rysä
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Leena
L
Kaikkonen
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Teemu
T
Karvonen
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Erja
E
Mustonen
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.
Raisa
R
Serpi
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Zoltán
Z
Szabó
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Olli
O
Tenhunen
Heart Center, Semmelweis University, Budapest, Hungary.
Zsolt
Z
Bagyura
Department of Pathology, The Institute of Diagnostics, University of Oulu, Oulu, Finland.
Juha
J
Näpänkangas
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Pauli
P
Ohukainen
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Pasi
P
Tavi
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.
Risto
R
Kerkelä
Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Cardiology, Skåne University Hospital, Malmö, Sweden.
Margrét
M
Leósdóttir
Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Björn
B
Wahlstrand
Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Thomas
T
Hedner
Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
Olle
O
Melander
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland; Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
Heikki
H
Ruskoaho
D000328:Adult; D000483:Alleles; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D055551:HSP27 Heat-Shock Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C517873:WDR12 protein, human; D048051:p38 Mitogen-Activated Protein Kinases