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：我们分析了活性氧（ROS）对成年大鼠心肌细胞肥大信号的调节功能。背景：ROS 调节多种细胞类型的有丝分裂信号转导。在新生大鼠心肌细胞中，抗​​氧化剂已被证明可以抑制心脏肥大，并且活性氧被认为可以调节肥大信号传导。但由于新生儿与成年心肌细胞的性质不同，该结论可能不能反映成熟心脏的情况。 方法：用内皮素-1（ET-1）或去氧肾上腺素（PE）刺激培养的成年大鼠心肌细胞，检查细胞内 ROS 水平、丝裂原激活蛋白激酶（MAPK；ERK、p38 和 JNK）的活性以及 3H-苯丙氨酸掺入。我们还检查了心肌细胞的抗氧化剂预处理对 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。 结果：ET-1 或 PE 刺激的心肌细胞中的 ROS 水平在 5 时最大增加。刺激后分钟。 ROS 的来源似乎来自 NADH/NADPH 氧化酶，因为用 NADH/NADPH 氧化酶抑制剂二亚苯基碘鎓预处理心肌细胞可抑制 ROS 的增加。 ET-1 或 PE 的刺激可增加细胞外信号调节激酶 (ERK) 活性。相比之下，p38 和 c-Jun-N 末端蛋白激酶 (JNK) 活性在这些刺激后没有变化。肌细胞的抗氧化处理抑制了 ROS 的增加，并阻止了 ERK 激活和随后由这些刺激诱导的心脏肥大。结论：这些数据表明，ROS 介导成年大鼠心肌细胞中 ET-1 或 PE 诱导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。