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

• Published in: PloS one Vol. 10; no. 4; p. e0124907
• Main Authors: Moilanen, Anne-Mari, Rysä, Jaana, Kaikkonen, Leena, Karvonen, Teemu, Mustonen, Erja, Serpi, Raisa, Szabó, Zoltán, Tenhunen, Olli, Bagyura, Zsolt, Näpänkangas, Juha, Ohukainen, Pauli, Tavi, Pasi, Kerkelä, Risto, Leósdóttir, Margrét, Wahlstrand, Björn, Hedner, Thomas, Melander, Olle, Ruskoaho, Heikki
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.04.2015; Public Library of Science (PLoS)
• Subjects: 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0124907

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.