The Change of Hypertrophic Signaling during the Development of Cardiac Hypertrophy and Its Regulation by Reactive Oxygen Species

心肌肥厚发生过程中肥厚信号的变化及其活性氧的调节

• 批准号: 12670670
• 负责人: TANAKA Koichi
• 金额: $ 2.05万
• 依托单位: Shimane Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670670/
• 关键词: cardic hypertrophy; reactive oxygen species; MAPK; MAPK

OBJECTIVES : We analyzed the regulatory function of reactive oxygen species (ROS) on the hypertrophic signaling in adult rat cardiac myocytes.BACKGROUND : The ROS regulate mitogenic signal transduction in various cell types. In neonatal rat cardiac myocytes, antioxidants have been shown to inhibit cardiac hypertrophy, and ROS are suggested to modulate the hypertrophic signaling. However, the conclusion may not reflect the situation of mature heart, because of the different nature between neonatal and adult cardiac myocytes.METHODS : Cultured adult rat cardiac myocytes were stimulated with endothelin-1 (ET-1) or phenylephrine (PE), and intracellular ROS levels, the activities of mitogen-activated protein kinases (MAPKs ; ERK, p38, and JNK), and 3H-phenylalanine incorporation were examined. We also examined the effects of antioxidant pretreatment of myocytes on MAPK activities and cardiac hypertrophy to analyze the modulatory function of redox state on MAPK-mediated hypertrophic signaling.RESULTS : The ROS levels in ET-1 or PE-stimulated myocytes were maximally increased at 5 min after stimulation. The origin of ROS appears to be from NADH/NADPH oxidase, because the increase in ROS was suppressed by pretreatment of myocytes with NADH/NADPH oxidase inhibitor diphenyleneiodonium. Extracellular signal-regulated kinase (ERK) activity was increased by the stimulation of ET-1 or PE. In contrast, p38 and c-Jun-N-terminal protein kinase (JNK) activities did not change after these stimulation. Antioxidant treatment of myocytes suppressed the increase in ROS and blocked ERK activation and subsequent cardiac hypertrophy induced by these stimuli.CONCLUSIONS : These data demonstrate that ROS mediate signal transduction of cardiac hypertrophy induced by ET-1 or PE in adult rat cardiac myocytes.

目的：我们分析了成年大鼠心肌细胞肥厚信号传导中活性氧（ROS）的调节功能。背景：ROS调节各种细胞类型的有丝分裂信号转导。在新生大鼠心脏肌细胞中，已证明抗氧化剂可以抑制心脏肥大，并建议ROS调节肥厚的信号传导。然而，由于新生儿和成人心肌细胞之间的性质不同，因此结论可能无法反映成熟心脏的状况。方法：培养的成年大鼠心肌细胞被内皮素-1（ET-1）或苯肾上腺素（PE）和苯肾上腺素（PE）和细胞内ROS水平，p3蛋白酶（p3 smap）和eRk; Erkins; Erkins; Erkins; Erk; Erk;检查了3H-苯基丙氨酸掺入。我们还研究了肌细胞抗氧化剂预处理对MAPK活性和心脏肥大的影响，以分析氧化还原状态对MAPK介导的肥大信号的调节功能。在5分钟内，ET-1或PE刺激的肌细胞中的ROS水平在5分钟内刺激后5分钟升高。 ROS的起源似乎来​​自NADH/NADPH氧化酶，因为通过使用NADH/NADH/NADPH氧化酶抑制剂二苯基二烯二氧化碳的心肌细胞预处理ROS的增加得到了抑制。通过刺激ET-1或PE，增加细胞外信号调节激酶（ERK）活性。相反，这些刺激后，p38和C-Jun-N-末端蛋白激酶（JNK）活性没有改变。肌细胞的抗氧化剂治疗抑制了这些刺激诱导的ROS的增加，并阻断了ERK激活和随后的心脏肥大。结论：这些数据表明，ROS介导了成年大鼠心脏肌细胞中ET-1或PE引起的心脏肥大的信号转导。

项目成果

Koichi Tanaka: "Redox Regulation of MAPK Pathways and Cardiac Hypertrophy in Adult Rat Cardiac Myocyte"J Am Coll Cardiol. 37. 676-85 (2001)

Koichi Tanaka：“成年大鼠心肌细胞中 MAPK 通路和心脏肥大的氧化还原调节”J Am Coll Cardiol。

Tanaka K,Honda M,Takabatake T: "Redox Regulation of MAPK Pathways and Cardiac Hypertrophy in Adult Rat Cardiac Myocyte"J Am Coll Cardiol. 37. 676-85 (2001)

Tanaka K、Honda M、Takabatake T：“成年大鼠心肌细胞中 MAPK 途径和心脏肥大的氧化还原调节”J Am Coll Cardiol。

Koichi Tanaka: "Redox Regulation of MAPK Pathways and Cardiac Hypertrophy in Adult Rat Cardiac Myocyte"Journal of the American College of Cardiology. 37. 676-685 (2001)

Koichi Tanaka：“成年大鼠心肌细胞中 MAPK 通路和心脏肥大的氧化还原调节”美国心脏病学会杂志。