Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, 08028 Barcelona, Spain.
J Mol Cell Cardiol. 2012 Oct;53(4):521-31. doi: 10.1016/j.yjmcc.2012.07.019.
The deacetylase Sirtuin-1 (Sirt1) is involved in the cardiac hypertrophic responses and cardiac embryo morphogenesis. However, the physiological function of Sirt1 deficiency in the postnatal development of the heart remains to be characterized. The aim of the study was to investigate the relevance of Sirt1 in the development and function of the myocardium. Hearts from Sirt1-deficient mice partially or totally lacking Sirt1 protein activity were analyzed. Loss of Sirt1 activity led to dilated cardiomyopathy in adult hearts, a phenotype accompanied by reduced cardiomyocyte size and the absence of fibrosis. Morphological and functional mitochondrial abnormalities were observed in the adult hearts lacking Sirt1, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Moreover, gene expression analyses revealed that mitochondrial genes were the most affected in Sirt1-deficient mice, showing a reduction in their expression. No overt cardiac dilatation was observed in neonates lacking Sirt1 activity, but first signs of mitochondrial alterations were already present. Immunoblot analyses revealed that Sirt1 is highly expressed in the heart after birth, indicating the importance of Sirt1 in the neonatal period. Finally, Sirt1 deficiency affected the acetylation pattern of the myocyte enhancer factor 2 (Mef2) transcription factors, which are critical for normal heart development and mitochondrial integrity. Collectively, our findings indicate that Sirt1 is essential for the maintenance of cardiac mitochondrial integrity and normal postnatal myocardium development.
去乙酰化酶 Sirtuin-1（Sirt1）参与心脏肥厚反应和心脏胚胎形态发生。然而，Sirt1 缺乏在心脏出生后发育中的生理功能仍有待阐明。本研究旨在探讨 Sirt1 在心肌发育和功能中的相关性。分析了 Sirt1 缺陷小鼠的心脏，这些小鼠部分或完全缺乏 Sirt1 蛋白活性。Sirt1 活性的丧失导致成年心脏扩张型心肌病，其表型伴有心肌细胞大小减小和无纤维化。在缺乏 Sirt1 的成年心脏中观察到形态和功能线粒体异常，表明线粒体功能障碍导致观察到的心肌病进展。此外，基因表达分析显示，线粒体基因在 Sirt1 缺陷小鼠中受影响最大，其表达减少。缺乏 Sirt1 活性的新生儿心脏未见明显扩张，但已存在线粒体改变的早期迹象。免疫印迹分析显示，Sirt1 在出生后心脏中高度表达，表明 Sirt1 在新生儿期的重要性。最后，Sirt1 缺乏影响肌细胞增强因子 2（Mef2）转录因子的乙酰化模式，该转录因子对于正常心脏发育和线粒体完整性至关重要。总之，我们的研究结果表明，Sirt1 对于维持心脏线粒体完整性和正常出生后心肌发育至关重要。
