β-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice.
β-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice.
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DOI：
10.1161/circresaha.112.280399
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发表时间：
2013-04-26
影响因子：
20.1
通讯作者：
Langenbach R
中科院分区：
文献类型：
--
作者：
Trivedi DB;Loftin CD;Clark J;Myers P;DeGraff LM;Cheng J;Zeldin DC;Langenbach R
腹主动脉瘤（AAA）是一种慢性炎症性血管疾病，目前尚无药物治疗方法。 AAA 形成的小鼠模型涉及长期输注血管紧张素 II (AngII)，之前的研究表明血管紧张素 II 1a 型 (AT1a) 受体在 AAA 形成中起主要作用。 β-arrestin-2 (βarr2) 是一种多功能支架蛋白，可结合 G 蛋白偶联受体（例如 AT1a），并调节多种信号传导途径和病理生理过程。然而，βarr2 在 AngII 诱导的 AAA 形成中的作用目前尚不清楚。确定 βarr2 是否在 AngII 诱导的小鼠 AAA 形成中发挥作用。用 AngII 治疗高脂血症 ApoE-/- 背景或正常脂血症 C57BL/6 背景的 βarr2+/+ 和 βarr2-/- 小鼠 28 天表明 βarr2 缺陷显着减弱 AAA 形成。 βarr2 缺陷减弱了 AngII 诱导的环氧合酶-2 (COX-2)、单核细胞趋化蛋白-1 (MCP-1)、巨噬细胞炎症蛋白 1α (MIP1α) 的表达和巨噬细胞浸润。 AngII 还增加了 ApoE-/-/βarr2+/+ 主动脉中磷酸化细胞外信号调节激酶 1/2 (p-ERK1/2) 的水平，而 βarr2 缺乏则减弱了这种增加。此外，用 CI1040（100mg/kg/天）抑制 ERK1/2 激活，可将 ApoE-/-/βarr2+/+ 小鼠中 AngII 诱导的 COX-2 表达水平降低至 ApoE-/-/βarr2-/- 小鼠中观察到的水平。 AngII 治疗还增加了 ApoE-/-/βarr2+/+ 主动脉中基质金属蛋白酶 (MMP) 的表达和弹性层的破坏，而 βarr2 缺乏则减少了这些影响。 βarr2 通过 p-ERK1/2 介导的 COX-2 诱导和增加炎症，促进 AngII 诱导的小鼠 AAA 形成。这些研究表明，对于 AT1a 受体，不依赖于 G 蛋白、依赖于 βarr2 的信号传导在 AngII 诱导的 AAA 形成中发挥着重要作用。
Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII) and previous studies indicated a primary role for the angiotensin II type 1a (AT1a) receptor, in AAA formation. β-arrestin-2 (βarr2) is a multifunctional scaffolding protein that binds G-protein coupled receptors such as AT1a, and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown. To determine if βarr2 played a role in AngII-induced AAA formation in mice. Treatment of βarr2+/+ and βarr2-/- mice on the hyperlipidemic ApoE-/- background or normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1α (MIP1α), and macrophage infiltration. AngII also increased the levels of phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2) in ApoE-/-/βarr2+/+ aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of ERK1/2 activation with CI1040 (100mg/kg/day) reduced the level of AngII-induced COX-2 expression in ApoE-/-/βarr2+/+ mice to the level observed in ApoE-/-/βarr2-/- mice. AngII treatment also increased matrix metalloproteinase (MMP) expression and disruption of the elastic layer in ApoE-/-/βarr2+/+ aortas and βarr2-deficiency reduced these effects. βarr2 contributes to AngII-induced AAA formation in mice by p-ERK1/2-mediated COX-2 induction and increased inflammation. These studies suggest that for the AT1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.