Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis
Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis
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DOI：
10.1152/ajplung.00222.2010
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发表时间：
2011-09-01
影响因子：
4.9
通讯作者：
Abdul-Hafez, Amal
中科院分区：
文献类型：
--
作者：
Uhal, Bruce D.;Li, Xiaopeng;Abdul-Hafez, Amal
[10]李X，薛A，高X，Abdul-Hafez A. ACE-2/血管紧张素1-7/Mas轴对肺泡上皮细胞存活的调节美国生理学杂志肺细胞分子生理学301：L269-L274，2011年。首次发表于2011年6月10日; doi：10.1152/ajplung.00222.2010.-本实验室的早期工作表明，肺泡上皮细胞（AEC）的凋亡需要自分泌产生血管紧张素（ANG）II。最近的研究表明，血管紧张素转换酶-2（ACE-2），其降解ANGII形成ANG 1 -7，是保护性的，但在人类和实验性肺纤维化中严重下调。因此，ACE-2及其产物ANG 1 -7可能调节AEC凋亡。为了评估这一假设，将AEC细胞系MLE-12和大鼠AEC的原代培养物暴露于促纤维化凋亡诱导剂ANGII或博来霉素（Bleo）。此后测量凋亡标志物（半胱天冬酶-9或-3活化和核碎裂）、稳态ANGII和ANG 1 -7以及JNK磷酸化。在Bleo不存在的情况下，通过小干扰RNA或竞争性抑制剂（DX 600肽）抑制ACE-2引起细胞培养基中自分泌ANGII的相互增加和ANG 1 -7的相应减少（均P < 0.05），并且诱导AEC凋亡。在基线（无抑制剂），培养基中的ANG 1 -7比ANGII高10倍（P < 0.01）。在培养的AEC中加入纯化的ANGII或博来霉素诱导的半胱天冬酶活化、核碎裂和JNK磷酸化。然而，与ANG 1 -7（0.1 μ M）预孵育阻止JNK磷酸化和凋亡。此外，用A779（一种ANG 1 -7受体mas的特异性阻断剂）预处理可阻止ANG 1 -7阻断JNK磷酸化、半胱天冬酶活化和核碎裂。这些数据表明ACE-2通过平衡促细胞凋亡ANGII及其抗细胞凋亡降解产物ANG 1 -7来调节AEC存活。他们还表明，ANG 1 -7通过ANG 1 -7受体质量抑制AEC凋亡。
Uhal BD, Li X, Xue A, Gao X, Abdul-Hafez A. Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis. Am J Physiol Lung Cell Mol Physiol 301: L269-L274, 2011. First published June 10, 2011; doi:10.1152/ajplung.00222.2010.-Earlier work from this laboratory demonstrated that apoptosis of alveolar epithelial cells (AECs) requires autocrine generation of angiotensin (ANG) II. More recent studies showed that angiotensin converting enzyme-2 (ACE-2), which degrades ANGII to form ANG1-7, is protective but severely downregulated in human and experimental lung fibrosis. Here it was theorized that ACE-2 and its product ANG1-7 might therefore regulate AEC apoptosis. To evaluate this hypothesis, the AEC cell line MLE-12 and primary cultures of rat AECs were exposed to the profibrotic apoptosis inducers ANGII or bleomycin (Bleo). Markers of apoptosis (caspase-9 or -3 activation and nuclear fragmentation), steady-state ANGII and ANG1-7, and JNK phosphorylation were measured thereafter. In the absence of Bleo, inhibition of ACE-2 by small interfering RNA or by a competitive inhibitor (DX600 peptide) caused a reciprocal increase in autocrine ANGII and corresponding decrease in ANG1-7 in cell culture media (both P < 0.05) and, moreover, induced AEC apoptosis. At baseline (without inhibitor), ANG1-7 in culture media was 10-fold higher than ANGII (P < 0.01). Addition of purified ANGII or bleomycin-induced caspase activation, nuclear fragmentation, and JNK phosphorylation in cultured AECs. However, preincubation with ANG1-7 (0.1 mu M) prevented JNK phosphorylation and apoptosis. Moreover, pretreatment with A779, a specific blocker of the ANG1-7 receptor mas, prevented ANG1-7 blockade of JNK phosphorylation, caspase activation, and nuclear fragmentation. These data demonstrate that ACE-2 regulates AEC survival by balancing the proapoptotic ANGII and its antiapoptotic degradation product ANG1-7. They also suggest that ANG1-7 inhibits AEC apoptosis through the ANG1-7 receptor mas.