Freeman E J, Chisolm G M, Ferrario C M, Tallant E A
Department of Internal Medicine, Akron (Ohio) General Medical Center, USA.
Hypertension. 1996 Jul;28(1):104-8. doi: 10.1161/01.hyp.28.1.104.
Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [3H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 mumol/L, with a maximal inhibition of 60% by 1 mumol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 mumol/L Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT1) or type 2 (AT2) receptors; however, [Sar1,Ile1]Ang II and [Sar1,Thr2]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [3H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 mumol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT1 antagonist losartan or L-158,809 but not AT2 antagonists blocked [3H]thymidine incorporation by Ang II. These results suggest that Ang-(1-7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT1 or AT2 receptor antagonists.
尽管血管紧张素II（Ang II）和七肽Ang-(1-7)仅相差一个氨基酸，但这两种肽在血管平滑肌细胞中产生不同的反应。我们之前表明，Ang II刺激磷酸肌醇水解，而Ang II和Ang-(1-7)释放前列腺素。我们现在报告，Ang II和Ang-(1-7)对大鼠主动脉血管平滑肌细胞生长的调节作用不同。Ang-(1-7)抑制[3H]胸腺嘧啶核苷掺入，这是对胎牛血清、血小板衍生生长因子或Ang II刺激的反应。Ang-(1-7)对血清刺激的胸腺嘧啶核苷掺入的抑制作用取决于七肽在1 nmol/L至1 μmol/L范围内的浓度，1 μmol/L Ang-(1-7)的最大抑制率为60%。Ang-(1-7)还将血清刺激的细胞数量增加抑制到最大77%（1 μmol/L Ang-(1-7)）。Ang-(1-7)对血清刺激的胸腺嘧啶核苷掺入的减弱不受血管紧张素1型（AT1）或2型（AT2）受体选择性拮抗剂的影响；然而，[Sar1,Ile1]Ang II和[Sar1,Thr2]Ang II是有效的拮抗剂，表明Ang-(1-7)的生长抑制是血管紧张素受体激活的结果。相反，在相同浓度范围内，Ang II刺激培养的血管平滑肌细胞中的[3H]胸腺嘧啶核苷掺入，1 μmol/L Ang II时的最大刺激率为314%。Ang II还增加了细胞总数（至对照的145%），表明增强的胸腺嘧啶核苷掺入与血管平滑肌细胞增殖有关。AT1拮抗剂氯沙坦或L-158,809可阻断Ang II引起的[3H]胸腺嘧啶核苷掺入，但AT2拮抗剂则不能。这些结果表明，Ang-(1-7)和Ang II在血管平滑肌细胞生长调节方面表现出相反的作用。Ang-(1-7)对增殖的抑制似乎是由一种新型血管紧张素受体介导的，该受体不受AT1或AT2受体拮抗剂的抑制。
