l'institut du thorax, Unité Inserm UMR 1087/CNRS UMR 6291, Nantes, France.
PLoS One. 2013 May 31;8(5):e64711. doi: 10.1371/journal.pone.0064711. Print 2013.
The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model.
Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg x kg(-1)) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific β-AR stimulations at d35.
At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β3-AR expression was only decreased at d70 (-37±8%). At d35, β1-AR expression was decreased by 68±6%, but ex vivo β1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β2-AR response in Dox-CM hearts, suggesting a decoupling of β2-AR to Gi protein.
This study highlights the β1/β2-AR imbalance in early Dox-CM and reveals the important role that β2-AR/Gi coupling could play in this pathology. Our results suggest that β2-AR could be an interesting target at early stage of Dox-CM.
阿霉素的毒性导致不可逆性心力衰竭，限制了其作为化疗药物的应用。早期使用β受体阻滞剂对阿霉素引起心力衰竭的患者有益，这表明β肾上腺素受体（β-AR）具有重要作用。本研究旨在鉴定一种假定的靶点（β-AR 及其效应器）在大鼠慢性阿霉素诱导的心肌病（Dox-CM）的早期阶段。
通过六次阿霉素注射（累积剂量：15mg x kg(-1)）诱导 Dox-CM，并通过超声心动图和左心室（LV）导管插入术进行验证。在第一次阿霉素注射后第 35 天（d35）和第 70 天（d70），通过 Western-blot 评估 LV 中β-AR 蛋白的表达。在 d35 时，通过分离心脏对特定β-AR 刺激的反应评估离体心脏的心肌收缩性（dP/dtmax，dP/dtmin）。
在 d35 时，Dox-CM 心脏表现为轻度 LV 收缩和舒张功能障碍，在 d70 时加重。在 Dox-CM 心脏中，β3-AR 表达仅在 d70 时减少（-37±8%）。在 d35 时，β1-AR 表达减少了 68±6%，但由于至少部分原因是通过评估 forskolin的腺苷酸环化酶反应增加，体外β1-AR 功能得以保留。β2-AR 表达在 d35（+58±22%）和 d70（+174±35%）时均增加，并且在 d35 时增加了体外β2-AR 反应。用百日咳毒素抑制 Gi 蛋白不影响 Dox-CM 心脏中的β2-AR 反应，表明β2-AR 与 Gi 蛋白解耦。
本研究强调了早期 Dox-CM 中的β1/β2-AR 失衡，并揭示了β2-AR/Gi 偶联在该病理中的重要作用。我们的结果表明，β2-AR 可能是 Dox-CM 早期阶段的一个有趣的靶点。
