Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure
Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure
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DOI：
10.1073/pnas.0602543103
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发表时间：
2006-09-26
影响因子：
11.1
通讯作者：
Pu, William T.
中科院分区：
文献类型：
--
作者：
Bisping, Egbert;Ikeda, Sadakatsu;Pu, William T.
心力衰竭发病机制中的一个重要事件是病理性心脏肥大的发展。在培养的心肌细胞中，激动剂诱导的心肌细胞肥大需要转录因子 Gata4。我们假设，在完整的有机体中，Gata4 是出生后心脏功能和心脏对病理应激的肥大反应的重要调节剂。为了验证这一假设，我们研究了 Gata4 (G4D) 第二外显子缺失的杂合小鼠。在基线时，G4D 小鼠有轻度收缩和舒张功能障碍，与心脏重量减轻和心肌细胞数量减少相关。横主动脉缩窄（TAC）后，G4D 小鼠出现明显的心力衰竭和离心性心脏肥大，并伴有纤维化和心肌细胞凋亡的显着增加。在 G4D 小鼠中，通过胰岛素样生长因子 1 受体过度表达来抑制细胞凋亡可预防 TAC 诱导的心力衰竭。与 WT-TAC 对照不同，G4D-TAC 心肌细胞通过长度增加超过宽度而肥大。基因表达谱揭示了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 对于出生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。
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 hypertrophied 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-beta 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.