Kruppel-like Factor 4 Protein Regulates Isoproterenol-induced Cardiac Hypertrophy by Modulating Myocardin Expression and Activity
Kruppel-like Factor 4 Protein Regulates Isoproterenol-induced Cardiac Hypertrophy by Modulating Myocardin Expression and Activity
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DOI：
10.1074/jbc.m114.582809
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发表时间：
2014-09-19
影响因子：
4.8
通讯作者：
Hayashi, Matsuhiko
中科院分区：
文献类型：
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作者：
Yoshida, Tadashi;Yamashita, Maho;Hayashi, Matsuhiko
Kruppel 样因子 4 (KLF4) 在血管疾病中发挥着重要作用，包括动脉粥样硬化和血管损伤。尽管除了血管细胞外，KLF4还在心脏中表达，但KLF4在心脏病中的作用尚未完全确定。本研究的目的是调查 KLF4 在心脏肥大中的作用并确定其潜在机制。心肌细胞特异性 Klf4 敲除 (CM Klf4 KO) 小鼠是通过 Cre/LoxP 技术产生的。长期输注β-肾上腺素受体激动剂异丙肾上腺素（ISO）可诱发心脏肥大。结果表明，与对照小鼠相比，CM Klf4 KO 小鼠中 ISO 诱导的心脏肥大增强。 CM Klf4 KO 小鼠的心脏加速肥大伴随着心肌细胞的增大以及胎儿心脏基因的过度表达，包括心房钠尿因子（Nppa）。此外，心肌素（一种调节胎儿心脏基因的转录辅助因子）的诱导在 CM Klf4 KO 小鼠中得到增强。有趣的是，KLF4通过调节心肌素的表达和活性来调节Nppa的表达，为CM Klf4 KO小鼠加速心脏肥大提供了力学基础。此外，我们发现 KLF4 介导了组蛋白脱乙酰酶抑制剂曲古抑菌素 A 的抗肥厚作用，因为 CM Klf4 KO 小鼠中 ISO 诱导的心脏肥大被奥美沙坦（一种血管紧张素 II 1 型拮抗剂）减弱，但曲古抑菌素 A 没有减弱作用。这些结果提供了新的证据，表明 KLF4 通过调节心肌素的表达和活性来调节心脏肥大。
Kruppel-like factor 4 (KLF4) plays an important role in vascular diseases, including atherosclerosis and vascular injury. Although KLF4 is expressed in the heart in addition to vascular cells, the role of KLF4 in cardiac disease has not been fully determined. The goals of this study were to investigate the role of KLF4 in cardiac hypertrophy and to determine the underlying mechanisms. Cardiomyocyte-specific Klf4 knockout (CM Klf4 KO) mice were generated by the Cre/LoxP technique. Cardiac hypertrophy was induced by chronic infusion of the beta-adrenoreceptor agonist isoproterenol (ISO). Results showed that ISO-induced cardiac hypertrophy was enhanced in CM Klf4 KO mice compared with control mice. Accelerated cardiac hypertrophy in CM Klf4 KO mice was accompanied by the augmented cellular enlargement of cardiomyocytes as well as the exaggerated expression of fetal cardiac genes, including atrial natriuretic factor (Nppa). Additionally, induction of myocardin, a transcriptional cofactor regulating fetal cardiac genes, was enhanced in CM Klf4 KO mice. Interestingly, KLF4 regulated Nppa expression by modulating the expression and activity of myocardin, providing a mechanical basis for accelerated cardiac hypertrophy in CM Klf4 KO mice. Moreover, we showed that KLF4 mediated the antihypertrophic effect of trichostatin A, a histone deacetylase inhibitor, because ISO-induced cardiac hypertrophy in CM Klf4 KO mice was attenuated by olmesartan, an angiotensin II type 1 antagonist, but not by trichostatin A. These results provide novel evidence that KLF4 is a regulator of cardiac hypertrophy by modulating the expression and the activity of myocardin.