Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy.
Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy.
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DOI：
10.1186/1479-5876-9-68
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发表时间：
2011-05-17
影响因子：
7.4
通讯作者：
Janssen PM
中科院分区：
文献类型：
--
作者：
Delfín DA;Xu Y;Peterson JM;Guttridge DC;Rafael-Fortney JA;Janssen PM
杜氏肌营养不良症（DMD）是一种遗传性和进行性疾病，导致横纹肌退化。20多岁的患者通常死于呼吸衰竭或心力衰竭。为了提高DMD患者的寿命和生活质量，重要的是防止或逆转心脏收缩功能的进行性丧失。我们实验室最近的研究表明，Nemo结合结构域（Nemo Binding Domain，NBD）肽靶向钝化核因子κB（NF-κB）信号传导，可减少炎症，增强肌纤维再生，并改善肌营养不良蛋白缺陷mdx小鼠膈肌的收缩缺陷。为了评估心脏功能以及隔膜功能是否可以得到改善，我们研究了用NBD肽处理的肌营养不良蛋白及其同系物肌营养不良蛋白缺陷的小鼠（双敲除= dko）的心肌的生理学和组织学参数。这些dko小鼠表现出心力衰竭的典型病理生理学特征，包括肌细胞变性、力-频率反应受损和β-肾上腺素能反应严重钝化。在离体心肌制备物中测量基线时的心脏收缩功能、整个体内范围内的频率和预负荷以及β-肾上腺素能储备。此外，我们研究了这些小鼠的组织病理学和炎症标志物。在基线条件下，来自NBD治疗的dko小鼠的心肌中的主动力发展是媒介物治疗的dko小鼠的两倍以上。NBD治疗还显著改善了肌肉的频率依赖性行为。与媒介物处理的小鼠相比，NBD处理的dko肌肉对β-肾上腺素能刺激的力的增加被稳健地恢复。然而，组织学特征，包括胶原蛋白含量和炎症标志物之间没有显着差异NBD治疗和车辆治疗的dko小鼠。我们的结论是，NBD可以显着改善心脏收缩功能障碍的dko小鼠模型的DMD，从而可能提供一种新的治疗心力衰竭的治疗。
Duchenne muscular dystrophy (DMD) is an inherited and progressive disease causing striated muscle deterioration. Patients in their twenties generally die from either respiratory or cardiac failure. In order to improve the lifespan and quality of life of DMD patients, it is important to prevent or reverse the progressive loss of contractile function of the heart. Recent studies by our labs have shown that the peptide NBD (Nemo Binding Domain), targeted at blunting Nuclear Factor κB (NF-κB) signaling, reduces inflammation, enhances myofiber regeneration, and improves contractile deficits in the diaphragm in dystrophin-deficient mdx mice. To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko) mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted β-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as β-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice. At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle-treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to β-adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice. We conclude that NBD can significantly improve cardiac contractile dysfunction in the dko mouse model of DMD and may thus provide a novel therapeutic treatment for heart failure.
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影响因子：
3.3
作者：
Lima-Cabello, Elena;Cuevas, Maria J.;Gonzalez-Gallego, Javier
通讯作者：
Gonzalez-Gallego, Javier
DOI：
10.1152/ajpheart.1995.269.2.h676
发表时间：
1995-08-01
影响因子：
4.8
作者：
JANSSEN, PML;HUNTER, WC
通讯作者：
HUNTER, WC
影响因子：
29.4
作者：
Shi, XZ;Pazdrak, K;Sarna, SK
通讯作者：
Sarna, SK
影响因子：
64.5
作者：
Deconinck, AE;Rafael, JA;Davies, KE
通讯作者：
Davies, KE
DOI：
10.1152/ajpheart.1996.271.1.h73
发表时间：
1996-07-01
影响因子：
4.8
作者：
deTombe, PP;Wannenburg, T;Little, WC
通讯作者：
Little, WC