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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure
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Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure

机译：需要Gata4来维持产后心脏功能并防止压力超负荷引起的心力衰竭

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摘要

An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiomyocytes, the transcription factor Gata4 is required for agonist-induced hypertrophy. We hypothesized that, in the intact organism, Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hy-pertrophied by increasing in length more than width. Gene expression profiling revealed up-regulation of genes associated with apoptosis and fibrosis, including members of the TGF-β pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure.
机译：心力衰竭发病机制中的重要事件是病理性心脏肥大的发展。在培养的心肌细胞中，激动剂诱导的肥大需要转录因子Gata4。我们假设，在完整的有机体中，Gata4是产后心脏功能以及心脏对病理应激的肥大反应的重要调节剂。为了检验该假设，我们研究了杂合子缺失Gata4第二外显子（G4D）的小鼠。在基线时，G4D小鼠患有轻度的收缩和舒张功能障碍，与体重减轻和心肌细胞数量减少有关。在横向主动脉缩窄（TAC）后，G4D小鼠出现明显的心力衰竭和离心性心肌肥大，与纤维化和心肌细胞凋亡显着增加有关。胰岛素样生长因子1受体的过表达抑制细胞凋亡可防止TAC诱发的G4D小鼠心力衰竭。与WT-TAC控件不同，G4D-TAC心肌细胞通过长度增加而不是宽度增加而肥大。基因表达谱分析显示与细胞凋亡和纤维化相关的基因上调，包括TGF-β途径的成员。我们的数据表明，Gata4对产后心脏的心脏功能至关重要。压力超负荷后，Gata4调节心肌细胞肥大的模式并保护心脏免受负荷引起的衰竭。

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