Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell
Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell
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DOI：
10.1172/jci316
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发表时间：
1998-04-01
影响因子：
15.9
通讯作者：
Anversa, P
中科院分区：
文献类型：
--
作者：
Leri, A;Claudio, PP;Anversa, P
物理力激活细胞凋亡和基因表达，但机制尚不清楚。为此，成年心肌细胞在等双轴拉伸装置中拉伸，并在4和24小时后检查细胞死亡的程度。牵张38 min、2、4、8、24 h后，心肌细胞凋亡率分别增加4.4倍和7.6倍，p53与血管紧张素原、AT（1）受体、酸性Bax启动子的结合也增加。牵张心肌细胞血管紧张素原、AT（1）受体、p53和Bax表达增加，Bcl-2表达减少。随着牵张时间的延长，AT、受体、p53、Bax和Bcl-2的变化越来越明显。培养液中的血管紧张素II浓度在10 min时增加，在1和20 h时达到最高水平。AT（1）阻断剂氯沙坦可抑制牵张心肌细胞的凋亡。肌细胞体积不受拉伸的影响。总之，拉伸介导的血管紧张素II的释放与细胞凋亡和p53的激活相结合，p53的激活可能是局部肾素-血管紧张素系统的长期上调和心肌细胞发生细胞凋亡的易感性增加的原因。
Physical forces activate apoptosis and gene expression, but the mechanism is unknown. For this purpose, adult myocytes were stretched in an equibiaxial stretch apparatus and the magnitude of cell death tvas examined 4 and 24 h later. The possibility of stretch-mediated activation of p53 and p53-dependent genes was evaluated at 38 min, 2, 4, 8, and 24 h, Myocyte apoptosis increased by 4.4- and 7.6-fold at 4 and 24 h after stretch, p53 binding to the promoter of angiotensinogen, AT(1) receptor, acid Bax also increased. Expression of angiotensinogen, AT(1) receptor, p53, and Bax increased and Bcl-2 decreased in stretched myocytes. The changes in AT, receptor, p53, Bax, and Bcl-2 became more apparent with the duration of stretch. Angiotensin II concentration in the medium increased at 10 min, reaching maximal levels at 1 and 20 h. The AT(1) blocker, losartan, abolished apoptosis in stretched myocytes. Myocyte volume was not influenced by stretch. In conclusion, stretch-mediated release of angiotensin II is coupled with apoptosis and the activation of p53 which may be responsible for the prolonged upregulation of the local renin-angiotensin system and the increased susceptibility of myocytes to undergo apoptosis.