Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure.
Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure.
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DOI：
10.1161/circresaha.110.217075
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发表时间：
2010-08-20
影响因子：
20.1
通讯作者：
Blaxall BC
中科院分区：
文献类型：
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作者：
Casey LM;Pistner AR;Belmonte SL;Migdalovich D;Stolpnik O;Nwakanma FE;Vorobiof G;Dunaevsky O;Matavel A;Lopes CM;Smrcka AV;Blaxall BC
通过心脏Gβγ亚基的过度信号传导是心力衰竭（HF）病理生理学的重要组成部分。它们在HF中将升高水平的胞质G蛋白偶联受体激酶2（GRK 2）募集至激动剂刺激的β-肾上腺素能受体（β-AR），导致慢性β-AR脱敏和下调;这些事件都是HF的标志。以前的数据表明，抑制Gβγ信号及其与GRK 2的相互作用可能对HF具有治疗价值。研究HF中小分子Gβγ抑制。我们最近描述了选择性阻断Gβγ结合相互作用的新型小分子Gβγ抑制剂，包括M119及其高度相关的类似物gallein。这些化合物在体外和HL 60细胞中阻断了Gβγ和GRK 2的相互作用。在这里，我们发现它们减少了β-AR介导的GRK 2在分离的成年小鼠心肌细胞中的膜募集。此外，M119增强腺苷酸环化酶活性和心肌细胞对β-AR激动剂的收缩反应。为了评价其体内心脏特异性作用，我们最初使用急性药理学HF模型（30 mg/kg/天异丙肾上腺素，7天）。每日同时注射预防了HF，并在该急性HF模型中部分正常化了心脏形态和GRK 2表达。为了研究阻止预先存在的HF进展的可能功效，患有现存HF的钙螯合蛋白心脏转基因小鼠（CSQ）接受每日注射，持续28天。单独使用该化合物可阻止HF进展，并使心脏大小、形态和HF标志物基因（GRK 2、ANF和β-MHC）的心脏表达部分正常化。这些数据表明，小分子抑制病理性Gβγ信号传导在治疗HF中具有很好的治疗作用。
Excess signaling through cardiac Gβγ subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G-protein coupled receptor kinase 2 (GRK2) to agonist-stimulated β-adrenergic receptors (β-ARs) in HF, leading to chronic β-AR desensitization and down-regulation; these events are all hallmarks of HF. Previous data suggested that inhibiting Gβγ signaling and its interaction with GRK2 could be of therapeutic value in HF. To investigate small molecule Gβγ inhibition in HF. We recently described novel small molecule Gβγ inhibitors that selectively block Gβγ binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of Gβγ and GRK2 in vitro and in HL60 cells. Here, we show they reduced β-AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to β-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially utilized an acute pharmacologic HF model (30 mg/kg/day isoproterenol, 7 days). Concurrent daily injections prevented HF, and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of pre-existing HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression, and partially normalized heart size, morphology and cardiac expression of HF marker genes (GRK2, ANF and β-MHC). These data suggest a promising therapeutic role for small molecule inhibition of pathologic Gβγ signaling in the treatment of HF.