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
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.
The Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
PLoS One. 2015 Apr 27;10(4):e0124907. doi: 10.1371/journal.pone.0124907. eCollection 2015.
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.
在最近一项全基因组关联研究中，WD重复结构域12（WDR12）与早发性心肌梗死（MI）相关。然而，WDR12在心脏中的功能尚不清楚。
我们对WDR12的心脏表达进行了表征，利用腺病毒介导的WDR12基因传递来研究WDR12对左心室（LV）重塑的影响，并分析了MI相关WDR12等位基因与人类受试者心脏功能之间的关系。扩张型心肌病患者和心肌梗死后大鼠的左心室WDR12蛋白水平升高。在正常成年大鼠心脏中，将WDR12基因导入左心室前壁可降低室间隔舒张期和收缩期厚度，并增加左心室舒张期和收缩期直径。此外，左心室射血分数（降低9.1%，P<0.05）和缩短分数（降低12.2%，P<0.05）。WDR12基因传递对心脏功能的不良影响与细胞增殖减少、p38丝裂原活化蛋白激酶（MAPK）/热休克蛋白（HSP）27途径激活以及核糖体生物合成所必需的增殖阻断1（BOP1）蛋白水平增加有关。心肌梗死后WDR12基因传递降低了E/A比值（降低32%，P<0.05），提示舒张功能恶化。在人类受试者中，MI相关WDR12等位基因与舒张功能障碍和左心房大小显著相关。
WDR12在成年大鼠心脏中引发明显的心脏功能恶化，且MI相关的WDR12变异体与人类受试者的舒张功能障碍有关。
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