Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart.
Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart.
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DOI：
10.1126/scitranslmed.3001909
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发表时间：
2011-09-14
影响因子：
17.1
通讯作者：
Kass DA
中科院分区：
文献类型：
--
作者：
Chakir K;Depry C;Dimaano VL;Zhu WZ;Vanderheyden M;Bartunek J;Abraham TP;Tomaselli GF;Liu SB;Xiang YK;Zhang M;Takimoto E;Dulin N;Xiao RP;Zhang J;Kass DA
心脏起搏治疗（CRT）是迄今为止唯一一种在临床上改善急性和慢性功能同时降低死亡率的心力衰竭（HF）治疗方法，其中对两个心室进行起搏，以重新协调因传导延迟而不同步的心脏收缩。CRT急性增强心室机械效率，但慢性改变肌细胞信号传导，包括改善β-肾上腺素能受体储备。我们推测，后者将确定独特的CRT效果，可能本身是有效的HF更普遍。通过6周的心房快速起搏（HFdys，左束消融）或无（HFsyn）不同步诱导犬HF。我们使用同步失调，然后进行同步快速起搏（每3周）进行CRT。HFdys和HFsyn肌细胞具有相似的抑制静息和β-肾上腺素能受体肌节和钙反应，特别是β2-肾上腺素能反应，而经受CRT的细胞表现与来自健康对照的细胞相似。CRT心肌细胞表现出与G蛋白（异源三聚体鸟嘌呤核苷酸结合蛋白）信号（RGS 2，RGS 3）调节剂增加相关的Gαi信号抑制，产生Gα s偏向的β2-肾上腺素能反应。这包括腺苷环AMP反应性增加和肌浆网定位蛋白激酶A的激活。人类CRT应答者也显示上调的肌细胞RGS 2和RGS 3。抑制Gαi（用百日咳毒素、RGS 3或RGS 2转染）、用Gα s偏向的β2激动剂（非诺特罗）刺激或短暂（2周）暴露于不同步状态使HFsyn中的β肾上腺素能受体反应恢复到CRT后获得的值。这些结果确定了通过恢复收缩同步性触发的关键途径，并且可能代表了广泛HF患者人群的新治疗方法。
Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling (RGS2, RGS3), yielding Gαs-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum–localized protein kinase A. Human CRT responders also showed up-regulated myo-cardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
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影响因子：
4.8
作者：
Roy, AA;Baragli, A;Chidiac, P
通讯作者：
Chidiac, P
影响因子：
--
作者：
Barth, Andreas S.;Aiba, Takeshi;Tomaselli, Gordon F.
通讯作者：
Tomaselli, Gordon F.
影响因子：
4.8
作者：
Rau, T;Nose, M;Eschenhagen, T
通讯作者：
Eschenhagen, T
影响因子：
37.8
作者：
Chakir K;Daya SK;Aiba T;Tunin RS;Dimaano VL;Abraham TP;Jaques-Robinson KM;Lai EW;Pacak K;Zhu WZ;Xiao RP;Tomaselli GF;Kass DA
通讯作者：
Kass DA
影响因子：
9.5
作者：
Babiker FA;Lorenzen-Schmidt I;Mokelke E;Vanagt WY;Delhaas T;Waltenberger J;Cleutjens JP;Prinzen FW
通讯作者：
Prinzen FW