Tu Victoria C, Bahl Joe J, Chen Qin M
Interdisciplinary Graduate Program in Pharmacology and Toxicology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
Cardiovasc Toxicol. 2003;3(2):119-33. doi: 10.1385/ct:3:2:119.
Cardiac hypertrophy is an adaptive response to a number of heart diseases including myocardial infarction. Although it can be compensatory at first, sustained hypertrophy is often a transition to heart failure. We have found that cardiomyocytes in culture can survive mild doses of H2O2 but develop hypertrophy involving activation of p70 S6 kinase 1 (p70S6K1). Here, the role of p42/p44(ERK) and p38 MAPK in oxidant-induced hypertrophy is tested. H2O2- induced phosphorylation (activation) of p42/p44(ERK) and p38 within 10 min of 200 microM H2O2 exposure. Although p42/p44(ERK) remained highly phosphorylated from 60 to 120 min, the level of p38 phosphorylation reached highest at 60 min and started to decline at 90 min. Inhibiting ERKs with PD98059 attenuated H2O2-induced AP-1 activation but did not affect H2O2-induced p70S6K1 activation or cardiomyocyte enlargement as measured by increases in cell volume and protein content. In contrast, the p38 inhibitor SB202190 has no inhibitory effect on AP-1 activation but partially prevented H2O2 from inducing p70S6K1 activation and cell enlargement. These data suggest that while p42/p44(ERK) participates in gene expression associated with hypertrophy, p38 may regulate cell size increase by p70S6K1 activation.
心脏肥大是对包括心肌梗死在内的多种心脏病的一种适应性反应。虽然它最初可能具有代偿作用，但持续的肥大往往是向心力衰竭转变的过程。我们发现，培养的心肌细胞在受到轻度剂量的过氧化氢（H2O2）时能够存活，但会发生肥大，涉及p70 S6激酶1（p70S6K1）的激活。在此，对p42/p44（细胞外信号调节激酶，ERK）和p38丝裂原活化蛋白激酶（MAPK）在氧化剂诱导的肥大中的作用进行了测试。在暴露于200微摩尔H2O2的10分钟内，H2O2诱导p42/p44（ERK）和p38磷酸化（激活）。虽然在60至120分钟内p42/p44（ERK）仍保持高度磷酸化，但p38磷酸化水平在60分钟时达到最高，并在90分钟时开始下降。用PD98059抑制ERK可减弱H2O2诱导的激活蛋白-1（AP-1）激活，但不影响H2O2诱导的p70S6K1激活或通过细胞体积和蛋白质含量增加所测量的心肌细胞增大。相反，p38抑制剂SB202190对AP-1激活没有抑制作用，但部分阻止了H2O2诱导p70S6K1激活和细胞增大。这些数据表明，虽然p42/p44（ERK）参与与肥大相关的基因表达，但p38可能通过激活p70S6K1来调节细胞大小增加。
