Intracellular angiotensin II induces cell proliferation independent of AT1 receptor
Intracellular angiotensin II induces cell proliferation independent of AT1 receptor
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DOI：
10.1152/ajpcell.00238.2006
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发表时间：
2006-11-01
影响因子：
5.5
通讯作者：
Kumar, Rajesh
中科院分区：
文献类型：
--
作者：
Baker, Kenneth M.;Kumar, Rajesh
我们最近报道了血管紧张素II（ANG II）对心肌细胞生长和肥大的内分泌作用，这种作用不受ANG II 1型受体（AT（1））拮抗剂氯沙坦的抑制。为了进一步确定AT 1在胞内分泌效应中的作用，我们研究了细胞内ANG II（iANG II）对天然中国仓鼠卵巢（CHO）细胞和稳定转染AT（1）受体（CHO-AT（1））的细胞增殖的影响。CHO-AT 1，而不是CHO细胞，显示出增强的增殖后，暴露于细胞外ANG II（eANG II）。然而，当用iANG II表达载体瞬时转染时，与用乱序肽转染的细胞相比，两种细胞类型均显示出显著增强的增殖。氯沙坦阻断eANG II诱导的细胞增殖，但不阻断iANG II诱导的细胞增殖。为了进一步证实这些发现，稳定转染CHO和CHO-AT（1）细胞用于iANG II表达（分别为CHO-iA和CHO-AT（1）-iA）。每24 h计数一次在无血清培养基中生长的细胞，直至72 h。CHO-iA和CHO-AT（1）-iA细胞的生长曲线分别比CHO和CHO-AT（1）更陡。这些观察结果通过Wst-1测定得到证实。AT（1）受体拮抗剂氯沙坦、缬沙坦、替米沙坦和坎地沙坦不能减弱CHO-iA和CHO-AT（1）-iA细胞的较快生长速率。eANG Ⅱ对CHO-AT（1）-iA细胞有明显的增殖作用，可被氯沙坦选择性阻断。这些数据表明，分泌内ANG II可以独立于AT（1）受体发挥作用，并提示ANG II的新的细胞内作用机制。
We recently reported intracrine effects of angiotensin II (ANG II) on cardiac myocyte growth and hypertrophy that were not inhibited by the ANG II type 1 receptor (AT(1)) antagonist, losartan. To further determine the role of AT1 in intracrine effects, we studied the effect of intracellular ANG II (iANG II) on cell proliferation in native Chinese hamster ovary (CHO) cells and those stably transfected with AT(1) receptor (CHO-AT(1)). CHO-AT1, but not CHO cells, showed enhanced proliferation following exposure to extracellular ANG II (eANG II). However, when transiently transfected with an iANG II expression vector, both cell types showed significantly enhanced proliferation, compared with those transfected with a scrambled peptide. Losartan blocked eANG II-induced cell proliferation, but not that induced by iANG II. To further confirm these findings, CHO and CHO-AT(1) cells were stably transfected for iANG II expression (CHO-iA and CHO-AT(1)-iA, respectively). Cells grown in serum-free medium were counted every 24 h, up to 72 h. CHO-iA and CHO-AT(1)-iA cells showed a steeper growth curve compared with CHO and CHO-AT(1), respectively. These observations were confirmed by Wst-1 assay. The AT(1) receptor antagonists losartan, valsartan, telmisartan, and candesartan did not attenuate the faster growth rate of CHO-iA and CHO-AT(1)-iA cells. eANG II showed an additional growth effect in CHO-AT(1)-iA cells, which could be selectively blocked by losartan. These data demonstrate that intracrine ANG II can act independent of AT(1) receptors and suggest novel intracellular mechanisms of action for ANG II.