Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates β-adrenergic receptor signaling and increases resting blood pressure
Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates β-adrenergic receptor signaling and increases resting blood pressure
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DOI：
10.1124/mol.61.4.749
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发表时间：
2002-04-01
影响因子：
3.6
通讯作者：
Koch, WJ
中科院分区：
文献类型：
--
作者：
Eckhart, AD;Ozaki, T;Koch, WJ
心血管调节受到 G 蛋白偶联受体 (GPCR) 信号传导的严格控制。 β-肾上腺素能受体 (AR) 是调节心脏正性肌力和变时性并介导血管舒张的 GPCR，这对全身血管阻力有重要影响。 GPCR 激酶 (GRK)，包括 GRK2（或 betaARK1），可使激动剂激活的 betaAR 磷酸化并使其脱敏。心力衰竭时心肌 GRK2 水平升高，数据表明高血压时血管水平也可能升高。因此，我们使用 SM22α 启动子的一部分生成了血管平滑肌 (VSM) 靶向过度表达 GRK2 的转基因小鼠，以确定其对血管 betaAR 调节的影响。通过腺苷酸环化酶和丝裂原激活蛋白 (MAP) 激酶激活测定确定，当 GRK2 过表达 2 至 3 倍时，VSM betaAR 信号传导减弱。使用异丙肾上腺素对 betaAR 刺激产生的体内血管舒张作用减弱，并且清醒静息平均动脉血压从非转基因同窝对照 (NLC) 小鼠 (n = 9) 的 96 +/- 2 mm Hg 升高到两个不同品系的 SM22α-GRK2 转基因小鼠 (n = 7 和 n = 7) 的 112 +/- 3 mm Hg 和 117 +/- 2 mm Hg。分别为 5；p < 0.05）。有趣的是，内侧 VSM 厚度从 NLC 小鼠 (n = 6) 的 29.8 +/- 1.6 μm 增加到 SM22 α-GRK2 小鼠 (n = 7) 的 39.4 +/- 1.6 μm (p < 0.05)，增加了 30%，并且血管 GRK2 过度表达足以引起心脏肥大。这些数据表明我们开发了一种独特的高血压小鼠模型，深入了解血管 betaAR 信号传导对静息血压和整体心血管调节的贡献。此外，他们表明GRK2在血管控制中发挥重要作用，并可能代表高血压的新治疗靶点。
Cardiovascular regulation is tightly controlled by signaling through G protein-coupled receptors (GPCRs). beta-Adrenergic receptors (ARs) are GPCRs that regulate inotropy and chronotropy in the heart and mediate vasodilation, which critically influences systemic vascular resistance. GPCR kinases (GRKs), including GRK2 (or betaARK1), phosphorylate and desensitize agonist-activated betaARs. Myocardial GRK2 levels are increased in heart failure and data suggest that vascular levels may also be elevated in hypertension. Therefore, we generated transgenic mice with vascular smooth muscle (VSM) targeted overexpression of GRK2, using a portion of the SM22alpha promoter, to determine its impact on vascular betaAR regulation. VSM betaAR signaling, as determined by adenylyl cyclase and mitogen-activated protein (MAP) kinase activation assays, was attenuated when GRK2 was overexpressed 2- to 3-fold. In vivo vasodilation in response to betaAR stimulation using isoproterenol was attenuated and conscious resting mean arterial blood pressure was elevated from 96 +/- 2 mm Hg in nontransgenic littermate control (NLC) mice (n = 9) to 112 +/- 3 mm Hg and 117 +/- 2 mm Hg in two different lines of SM22alpha-GRK2 transgenic mice (n = 7 and n = 5, respectively; p < 0.05). Interestingly, medial VSM thickness was increased 30% from 29.8 +/- 1.6 mu m in NLC mice (n = 6) to 39.4 +/- 1.6 mu m in SM22 alpha-GRK2 mice (n = 7) (p < 0.05) and vascular GRK2 overexpression was sufficient to cause cardiac hypertrophy. These data indicate that we have developed a unique mouse model of hypertension, providing insight into the contribution that vascular betaAR signaling makes toward resting blood pressure and overall cardiovascular regulation. Moreover, they suggest that GRK2 plays an important role in vascular control and may represent a novel therapeutic target for hypertension.