Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro.
Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro.
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DOI：
10.1042/bj3470275
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发表时间：
2000-04
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影响因子：
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通讯作者：
Hiroki Aoki;Mary Richmond;Seigo Izumo;Junichi Sadoshima
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文献类型：
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作者：
Hiroki Aoki;Mary Richmond;Seigo Izumo;Junichi Sadoshima
虽然MAP（丝裂原活化蛋白）激酶与许多细胞类型的细胞增殖和分化有关，但MAP激酶在心肌肥厚中的作用尚不清楚。我们检测了细胞外信号调节蛋白激酶（ERK）、c-Jun n -末端激酶（JNK）和p38 MAP激酶在新生大鼠心肌细胞血管紧张素II （Ang II）诱导的肥大和苯肾上腺素诱导的肥大中的作用。Ang II和苯肾上腺素对ERKs的激活程度相似，而苯肾上腺素对JNK和p38的激活比Ang II更强、更持久。PD98059是MAPK/ERK激酶（MEK）的特异性抑制剂，可抑制Ang ii诱导的心房钠尿因子（ANF） mRNA和多肽水平的表达，而苯肾上腺素诱导的心房钠尿因子（ANF）表达不受抑制。SB203580是p38和部分JNK亚型的特异性抑制剂，对Ang II或苯肾上腺素诱导的ANF表达无显著影响。虽然PD98059和显性阴性MEK1阻断了Ang ii诱导的ANF启动子的激活，但SB203580或显性阴性MEK激酶1 （MEKK1）没有作用。苯肾上腺素诱导的ANF启动子激活被SB203580和显性阴性MEKK1显著抑制，而PD98059和显性阴性MEK1不受抑制。显性阴性Ras抑制ERK激活和Ang II对ANF的上调，而组成型活性Ras和MEK则足以激活ANF启动子。显性阴性Ras也部分抑制了苯肾上腺素诱导的ANF启动子的激活。PD98059不影响Ang ii诱导的肥大的其他标志物，如骨骼α -肌动蛋白和c-fos的表达，蛋白质合成速度的增加或肌动蛋白的快速组织。这些结果表明Ang II通过ERK表达ANF，而苯肾上腺素通过其他途径表达ANF。Ras/ERK通路选择性地介导angii诱导的肥大中各种表型的ANF表达。ERK通路介导心肌肥大的激动剂特异性和表型特异性反应。
Although MAP (mitogen-activated protein) kinases are implicated in cell proliferation and differentiation in many cell types, the role of MAP kinases in cardiac hypertrophy remains unclear. We examined the role of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAP kinase in angiotensin II (Ang II)-induced hypertrophy compared with phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. Both Ang II and phenylephrine activated ERKs to a similar extent, whereas phenylephrine caused stronger and more sustained activation of JNK and p38 than Ang II. PD98059, a specific inhibitor of MAPK/ERK kinase (MEK),inhibited Ang II-induced, but not phenylephrine-induced, expression of atrial natriuretic factor (ANF) at both the mRNA and polypeptide levels. SB203580, a specific inhibitor of p38 and some JNK isoforms, did not show significant effects on ANF expression induced by Ang II or phenylephrine. Although PD98059 and dominant-negative MEK1 blocked Ang II-induced activation of the ANF promoter, SB203580 or dominant-negative MEK kinase 1 (MEKK1) showed no effect. Phenylephrine-induced ANF promoter activation was significantly inhibited by SB203580 and dominant-negative MEKK1, but not by PD98059 or dominant-negative MEK1. Dominant-negative Ras inhibited both ERK activation and ANF up-regulation by Ang II, whereas constitutively active forms of Ras and MEK were sufficient to activate the ANF promoter. Dominant-negative Ras also partly inhibited the phenylephrine-induced activation of ANF promoter. PD98059 did not affect other markers of Ang II-induced hypertrophy, such as skeletal alpha-actin and c-fos expression, increases in the rate of protein synthesis or rapid sarcomeric actin organization. These results suggest that Ang II uses ERK for ANF expression, whereas phenylephrine uses other pathways. The Ras/ERK pathway selectively mediates ANF expression in various phenotypes observed in Ang II-induced hypertrophy. The ERK pathway mediates an agonist-specific and phenotype-specific response in cardiac hypertrophy.