Angiotensin II Type 2 Receptor Inhibits Vascular Intimal Proliferation With Activation of PPARγ
Angiotensin II Type 2 Receptor Inhibits Vascular Intimal Proliferation With Activation of PPARγ
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DOI：
10.1093/ajh/hpv168
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发表时间：
2016-06-01
影响因子：
3.2
通讯作者：
Horiuchi, Masatsugu
中科院分区：
文献类型：
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作者：
Kukida, Masayoshi;Mogi, Masaki;Horiuchi, Masatsugu
血管紧张素Ⅱ 2型（AT（2））受体的刺激可以发挥有益的作用，血管重塑。先前，我们报道了AT（2）受体刺激改善糖尿病小鼠的胰岛素抵抗，同时伴有在血管系统中也起着各种关键作用的PPAR γ激活。因此，本研究旨在探讨AT（2）受体激活与AT（2）受体相互作用蛋白（ATIP）相关的过氧化物酶体增殖物激活受体γ（PPARgamma）的血管保护作用。用化合物21（C21）（AT（2）受体激动剂）治疗，降低了损伤动脉中的新生内膜形成、细胞增殖和单核细胞趋化蛋白-1（MCP-1）、肿瘤坏死因子（TNF）-α和白细胞介素-1 β的mRNA水平，以及核因子-κ B的磷酸化，并增加了PPAR γ DNA结合活性，而C21的这些抑制作用通过与PPAR γ拮抗剂GW 9662共处理而减弱。C21处理血管平滑肌细胞（VSMC），从smAT（2）转基因小鼠，其中高表达AT（2）受体的VSMC制备，增加了过氧化物酶体增殖物激活受体γ活性和DNA结合活性测定的双荧光素酶测定和电泳迁移率变动分析（EMSA），分别。我们观察到ATIP参与了PPARgamma复合物的形成，并且ATIP 1的siRNA转染减弱了AT（2）受体介导的VSMC中PPARgamma活性的增加。ATIP在AT（2）受体介导的PPAR γ激活中起重要作用，提示AT（2）受体激活PPAR γ可能是ATIP抑制血管内膜增生的一种新机制。
Angiotensin II type 2 (AT(2)) receptor stimulation could exert beneficial effects on vascular remodeling. Previously, we reported that AT(2) receptor stimulation ameliorated insulin resistance in diabetic mice accompanied by PPAR gamma activation which also plays a variety of crucial roles in the vasculature. Therefore, this study aimed to investigate the vascular protective effect of the AT(2) receptor with activation of PPAR gamma involving AT(2) receptor-interacting protein (ATIP).Vascular injury was induced by polyethylene-cuff placement around the femoral artery in C57BL/6J mice. Treatment with compound 21 (C21), an AT(2) receptor agonist, decreased neointimal formation, cell proliferation, and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-alpha, and interleukin-1 beta, and phosphorylation of nuclear factor-kappa B, and increased PPAR gamma DNA-binding activity in the injured artery, whereas these inhibitory effects of C21 were attenuated by co-treatment with a PPAR gamma antagonist, GW9662. Treatment of vascular smooth muscle cells (VSMC) with C21 prepared from smAT(2) transgenic mice, which highly express the AT(2) receptor in VSMC, increased both PPAR gamma activity and its DNA-binding activity determined by dual-luciferase assay and electrophoresis mobility shift assay (EMSA), respectively. We observed that ATIP was involved in PPAR gamma complex formation, and that transfection of siRNA of ATIP1 attenuated the AT(2) receptor-mediated increase in PPAR gamma activity in VSMC. In response to AT(2) receptor stimulation, ATIP was translocated from the plasma membrane to the nucleus.Our results suggest a new mechanism by which AT(2) receptor stimulation activates PPAR gamma, thereby resulting in amelioration of vascular intimal proliferation, and that ATIP plays an important role in AT(2) receptor-mediated PPAR gamma activation.