Adenosine A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to 1-adrenoceptor stimulation in vivo
Adenosine A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to 1-adrenoceptor stimulation in vivo
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DOI：
10.1111/bph.13339
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发表时间：
2016-01-01
影响因子：
7.3
通讯作者：
Devaux, Y.
中科院分区：
文献类型：
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作者：
Puhl, S-L;Kazakov, A.;Devaux, Y.
背景和目的腺苷已被提议发挥抗肥大作用。然而，心脏中不同腺苷受体亚型的精确调节和作用以及它们对肥大信号传导的影响在很大程度上尚不清楚。我们的目的是表征体外和体内肥大刺激后腺苷 A(1) 受体的表达和功能。实验方法新生大鼠心肌细胞和雄性 C57/Bl6 小鼠的促肥大刺激和腺苷 A1 受体刺激，皮下。本研究应用了给药、实时 PCR、3[H]-亮氨酸掺入测定、免疫染色、组织染色、蛋白质印迹、重量分析和超声心动图。 主要结果 在新生大鼠心肌细胞培养物中，去氧肾上腺素（而非血管紧张素 II 或胰岛素样生长因子 1 (IGF1)）上调腺苷 A1 受体浓度依赖性。选择性 A1 受体激动剂 N6-环戊基腺苷可以抵消去氧肾上腺素 (10 μM) 介导的肥大表型（心肌细胞大小、肌节组织、总蛋白合成、c-fos 表达），但血管紧张素 II (1 μM) 或 IGF1 (20 ng 中心点 mL-1) 介导的肥大表型不受影响。在 C57/BL6 小鼠中，连续 N6-环戊基腺苷输注（2mg 中心点 kg - (1-)day -1; 21 天）钝化去氧肾上腺素（120mg 中心点 kg (-1) .day (-1); 21 天）诱导肥大（心脏重量、心肌细胞大小和胎儿基因）、纤维化、MMP 2 上调和氧化应激的产生 - 所有适应不良重塑的标志。同时，给予去氧肾上腺素可增加腺苷A1受体的表达。结论和意义我们已经提出了负反馈机制的证据，该机制可减轻α(1)肾上腺素受体刺激后的病理性心肌肥大。我们的研究结果表明，腺苷 A(1) 受体可以作为治疗策略的潜在靶标，以防止由于慢性心脏压力超负荷而导致代偿性心肌肥大转变为失代偿性心力衰竭。
BACKGROUND AND PURPOSE Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of adenosine A(1) receptors following hypertrophic stimulation in vitro and in vivo.EXPERIMENTAL APPROACH Pro- hypertrophic stimuli and adenosine A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, sc. drug administration, real- time PCR, 3[ H]- leucine- incorporation assay, immunostaining, tissue staining, Western blots, gravimetric analyses and echocardiography were applied in this study.KEY RESULTS In neonatal rat cardiomyocyte cultures, phenylephrine, but not angiotensin II or insulin- like growth factor 1 ( IGF1), up- regulated adenosine A1 receptors concentration- dependently. The hypertrophic phenotype ( cardiomyocyte size, sarcomeric organization, total protein synthesis, c- fos expression) mediated by phenylephrine ( 10 mu M), but not that by angiotensinII ( 1 mu M) or IGF1 ( 20 ng center dot mL - 1), was counteracted by the selective A1 receptor agonist, N6- cyclopentyladenosine. In C57/ BL6 mice, continuous N6- cyclopentyladenosine infusion ( 2mg center dot kg - (1-)day -1; 21 days) blunted phenylephrine ( 120mg center dot kg (-1) .day (-1); 21 days) induced hypertrophy ( heart weight, cardiomyocyte size and fetal genes), fibrosis, MMP 2 up- regulation and generation of oxidative stress - all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased expression of adenosine A1 receptors.CONCLUSIONS AND IMPLICATIONS We have presented evidence for a negative feedback mechanism attenuating pathological myocardial hypertrophy following alpha(1)adrenoceptor stimulation. Our results suggest adenosine A(1) receptors as potential targets for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure overload.