GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.
GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.
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DOI：
10.1161/circulationaha.112.109868
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发表时间：
2012-12-11
期刊：
影响因子：
37.8
通讯作者：
Archer SL
中科院分区：
文献类型：
--
作者：
Piao L;Fang YH;Parikh KS;Ryan JJ;D'Souza KM;Theccanat T;Toth PT;Pogoriler J;Paul J;Blaxall BC;Akhter SA;Archer SL
右心室衰竭/肥大（RVH）中肾上腺素能信号传导受损的原因和后果知之甚少。我们假设G蛋白偶联受体激酶-2（GRK 2）介导的β-肾上腺素能受体信号的解偶联损害了正性肌力储备。测试了右心室（RV）肾上腺素能重塑对正性肌力药物选择的影响以及使用gallein中断Gβγ-GRK 2相互作用的治疗益处。在与肺动脉高压相关的啮齿动物RVH（PAH-RVH; SU 5416+慢性缺氧或野百合碱）与肺动脉捆扎诱导的RVH（PAB-RVH）中比较肾上腺素能重塑的室特异性和细胞定位。结果在10例PAH患者与对照的RV阵列中得到证实。在RV和左心室Langendorff模型和体内评估变力储备。评估了Gallein治疗（1.8 mg/kg/天×2周）。尽管RVH相似，但PAH-RVH的心输出量（58.3±4.9 vs 82.9±4.8 mL/min; P<0.001）和跑台距离（41.5±11.6 vs 244.1±12.4 m; P<0.001）低于PAB-RVH。与PAB-RVH相比，PAH-RVH中β1-、α1-和多巴胺-1受体的下调程度更大，左心室受累程度更高，RV收缩储备受损程度更大。RV GRK 2活性增加与肾上腺素能受体表达和正性肌力药刺激的cAMP水平降低平行（P<0.01）。在人PAH-RVH中也发生β1受体下调。多巴酚丁胺作为RV正性肌力药上级多巴胺，无论是体外还是体内。GRK 2介导的肾上腺素能和多巴胺能受体脱敏下调损害PAH-RVH的正性肌力储备RVH中的急性正性肌力支持最好由多巴酚丁胺完成，反映了其与腺苷酸环化酶的更好偶联以及多巴胺对多巴胺-1-受体信号传导的依赖，多巴胺-1-受体信号传导在RVH中受损。抑制Gβγ-GRK 2相互作用在RVH中具有治疗益处。
The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein–coupled receptor kinase-2 (GRK2)–mediated uncoupling of β-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ–GRK2 interaction, using gallein, were tested. Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding–induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular–Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 versus 82.9±4.8 mL/min; P<0.001) and treadmill distance (41.5±11.6 versus 244.1±12.4 m; P<0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of β1-, α1- and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (P<0.01). β1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo. GRK2-mediated desensitization-down-regulation of adrenergic and dopaminergic receptors impairs inotropic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1–receptor signaling, which is impaired in RVH. Inhibiting Gβγ–GRK2 interactions has therapeutic benefit in RVH.