Jin Xue-Qing, Fukuda Noboru, Su Jin-Zi, Lai Yi-Mu, Suzuki Ryo, Tahira Yoshiko, Takagi Hiroto, Ikeda Yukihiro, Kanmatsuse Katsuo, Miyazaki Hitoshi
Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Hypertension. 2002 May;39(5):1021-7. doi: 10.1161/01.hyp.0000016179.52601.b4.
Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT(1)) and type 2 (AT(2)), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT(1) receptor. To elucidate the direct effects of the AT(2) receptor on the AT(1) receptor in VSMCs, we transfected AT(2) receptor gene into cultured rat VSMCs. Overexpression of AT(2) receptor significantly decreased expression of AT(1a) receptor at both the mRNA and protein levels in the presence and absence of Ang II in VSMCs. Overexpression of AT(2) receptor increased expression of bradykinin and inducible NO in the presence and absence of Ang II in VSMCs. Bradykinin B(2) receptor antagonist HOE-140 and NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) inhibited the decreases in AT(1a) receptor expression by the overexpression of AT(2) receptor in VSMCs. L-Arginine augmented the decrease in AT(1a) receptor expression. Overexpression of AT(2) receptor suppressed basal DNA synthesis and proliferation of VSMCs and abolished response of DNA synthesis to Ang II in VSMCs. Our results demonstrate that overexpression of the AT(2) receptor downregulates AT(1a) receptor expression in rat VSMCs in a ligand-independent manner that is mediated by the bradykinin/NO pathway. Downregulation of AT(1a) receptor is a novel mechanism by which the AT(2) receptor regulates growth and metabolism of VSMCs.
已鉴定出血管紧张素（Ang）II受体的两种不同亚型，即1型（AT(1)）和2型（AT(2)）。血管平滑肌细胞（VSMC）通常表达AT(1)受体。为了阐明AT(2)受体对VSMC中AT(1)受体的直接作用，我们将AT(2)受体基因转染到培养的大鼠VSMC中。在VSMC中，无论有无Ang II，AT(2)受体的过表达均显著降低了AT(1a)受体在mRNA和蛋白水平的表达。在VSMC中，无论有无Ang II，AT(2)受体的过表达均增加了缓激肽和诱导型一氧化氮（NO）的表达。缓激肽B(2)受体拮抗剂HOE-140和NO合酶抑制剂N(ω)-硝基-L-精氨酸甲酯（L-NAME）抑制了VSMC中AT(2)受体过表达导致的AT(1a)受体表达降低。L-精氨酸增强了AT(1a)受体表达的降低。AT(2)受体的过表达抑制了VSMC的基础DNA合成和增殖，并消除了VSMC中DNA合成对Ang II的反应。我们的结果表明，AT(2)受体的过表达以一种不依赖配体的方式下调大鼠VSMC中AT(1a)受体的表达，该方式由缓激肽/NO途径介导。AT(1a)受体的下调是AT(2)受体调节VSMC生长和代谢的一种新机制。
