https://scholars.lib.ntu.edu.tw/handle/123456789/188177
標題: | 活性氧族群及一氧化氮於心臟細胞中調控內皮素所誘發乙型肌凝重鍊蛋白基因所扮演的角色 | 其他標題: | Role of r eactive oxygen species and nitr ic oxide in modulation of endothelin-1-induced beta-myosin heavy chain gene expr ession in cardiomyocytes. | 作者: | 陳錦澤 | 關鍵字: | 內皮素;活性氧族群;乙型重鏈基因;心臟細胞;細胞肥大;endothelin-1;reactive oxygen species;beta-myosin heavy chain gene;cardiomyocyte;hypertrophy | 公開日期: | 2002 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 大多數心血管方面的疾病,都會造成 心臟的肥大,初期的心臟肥大可以代償心 臟功能,然而持續性的心臟肥大,便會導 致心臟的衰竭。在心臟細胞,由於機械應 力或內生性生長因子的刺激作用下,會造 成心臟細胞的肥大,心臟細胞的過度肥大 有可能導致心臟機能受損,進一步引起心臟衰竭。內皮素(endothelin-1; ET-1)有 造成細胞肥大的作用,但對於此作用其細 胞內的機轉目前還不是很清楚,已知內皮 素可增加許多迅即基因如c-fos 、c-jun 及 egr-1 等的基因表現;另外,對一些與心 臟細胞的增大有關的基因如心房利鈉 (atrial natriuretic peptide)、肌凝蛋 白重鏈(myosin heavy chain)、骨骼肌肉 肌動蛋白(actin)等,也有增加它們基因表 現的作用。近來有許多研究報告指出活性 氧族群(r eactive oxygen species ;ROS )及一氧化氮(nitric oxide; NO)可於細胞內 扮演一訊號傳遞者的角色,所以在本研究 中,我們進一步觀察活性氧族群於內皮素 所誘發細胞肥大現象所扮演的角色,並進 而闡釋其可能的細胞內機轉。由本報告抗 氧化劑可抑制內皮素所誘發心臟細胞肥 大,可推測抗氧化劑,在臨床上相關心臟 肥大或心臟衰竭疾病的預防治療上具有運用潛力。 OBJECTIVES: We dissected the molecular regulatory mechanism of reactive oxygen species (ROS) on endothelin-1-( ET-1)-induced b-myosin heavy chain (b-MyHC) gene expression and hypertrophic signaling in neonatal rat cardiomyocytes. BACKGROUND: ET-1 causes hypertrophy in the cardiomyocytes. Expression of cardiac b-MyHC gene is increased in response to ET-1. Our previous study has demonstrated that ET-1 increases intracellular reactive oxygen species (ROS) in cardiomyocytes. However, the intracellular regulatory mechanism of ROS on ET-1-induced b-MyHC gene expression and cardiac hypertrophy still remains unclear. METHODS: Cultured neonatal rat cardiomyocytes were stimulated with ET-1, 3 H-leucine incorporation and the b-MyHC gene promoter activities were examined. We also examined the effects of antioxidant pretreatment on ET-1-induced cardiac hypertrophy and MAPK activties to elucidate the redox-sensitive pathway in cardiomyocyte hypertrophy and b-MyHC gene expression. RESULTS: 3 H-Leucine incorporation and b-MyHC promoter activities were increased by ET-1. These ET-1 effects were blocked by the specific ETA receptor antagonist BQ-485. Cardiomyocytes treated with antioxidants significantly reduced ET-1-induced 3 H-leucine incorporation and b-MyHC gene promoter activities. ET-1 activated mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase [ERK], p38, and JNK), which were significantly inhibited by antioxidants. Either PD98059 or SB203580 inhibited ET-1-increased 3 H-leucine incorporation, but only PD98059 decreased ET-1-induced b-MyHC promoter activities. Co-transfection of dominant negative mutant of Ras, Raf, and MEK1 decreased the ET-1-increased b-MyHC promoter activities, suggesting that the Ras-Raf-ERK pathway is required for ET-1 action. Deletion mapping revealed that the deletion construct containing 273 base pairs (bp) of b-MyHC 5’-flanking sequences upstream from the transcription initiation site is necessary and sufficient for ET-1-induced increase of transcription, whereas the construct containing only 188 bp of 5’-flanking region had no effect, indicating the ET-1-responsive element(s) is located between position -273 and –188 bp upstream from the transcription start site. This minimal construct of 273 bp upstream of transcription initiation site in the b-MyHC promoter region is also required for ROS-induced b-MyHC expression. CONCLUSIONS: These data demonstrate that ROS involved in ET-1-induced hypertrophic responses, b-MyHC expression and mediated ET-1-induced activation of MAPK pathways, which culminated in hypertrophic responses and b-MyHC expression. The ROS-MAPK (ERK)-meditated pathway plays an essential role in ET-1-induced hypertrophic responses and b-MyHC expression in cardiomyocytes. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23574 | 其他識別: | 902320B002144 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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