Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy
Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy
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DOI：
10.1093/cvr/cvu119
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发表时间：
2014-07-01
影响因子：
10.8
通讯作者：
Chen, Xiongwen
中科院分区：
文献类型：
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作者：
Li, Ying;Zhang, Shuai;Chen, Xiongwen
为了确定β-肾上腺素能反应的改变是否会导致人类杜氏肌营养不良症动物模型mdx（X连锁肌营养不良症）小鼠的早期心脏功能障碍。mdx心脏的替代纤维化随着年龄的增长而逐渐增加，表明心肌细胞逐渐丧失。超声心动图和左心室内血流动力学测量检测到mdx小鼠的基线心功能不全，剂量为千分之一日元8个月。然而，在4个月时，mdx小鼠中已经存在对异丙肾上腺素（ISO）的心脏β-肾上腺素能反应降低。从4月龄和8月龄mdx小鼠分离的心室肌细胞（VM）的基线收缩功能{缩短分数、[Ca 2 +]（i）和肌浆网（SR）Ca 2+含量}和ICa-L大于年龄匹配的对照VM和从2月龄mdx小鼠分离的心肌细胞。ISO增加了4个月和8个月大mdx小鼠VM中的肌细胞功能，达到与年龄匹配的对照VM相同的水平。在12月龄mdx小鼠的VM中，ISO未能将心肌细胞功能提高到12月龄对照小鼠VM中的水平，并且不能进一步增加I（Ca-L）。Cav1.2 α 1c、Cav1.2 β 1、Cav1.2 β 2、肌浆网/内质网Ca 2 + ATP酶（SERCA）和Na+/Ca 2+交换器的表达无差异。相比之下，总Ryanodine受体2（RyR 2）和RyR 2，受磷蛋白和Cav1.2 α 1c的基础磷酸化被发现在4个月大的mdx小鼠的心脏增加;基线蛋白激酶A活性也增加。ISO处理后，mdx和对照心脏中的磷酸化水平相同。4月龄mdx小鼠VM β 1-肾上腺素能受体（β 1-AR）密度和β-肾上腺素能敏感性降低，而年轻mdx小鼠心肌细胞收缩功能增强，以补偿心肌细胞损失。然而，这些基线功能增强的肌细胞刺激潜力降低，β 1-AR密度/敏感性降低，导致心脏β-肾上腺素能反应减弱。
To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at a parts per thousand yen8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca2+](i), and sarcoplasmic reticulum (SR) Ca2+ content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseI(Ca-L). No differences were observed in the expression of Cav1.2 alpha 1c, Cav1.2 beta 1, Cav1.2 beta 2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and the Na+/Ca2+ exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2 alpha 1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (beta 1-AR) density and beta-adrenergic sensitivity.In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased beta 1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.