Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction.
Melusin protects from cardiac rupture and improves functional remodelling after myocardial infarction.
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DOI：
10.1093/cvr/cvt235
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发表时间：
2014
影响因子：
10.8
通讯作者：
Bernhard W. Unsöld;Axel Kaul;Mauro Sbroggió;Carola Schubert;V. Regitz-Zagrosek;M. Brancaccio;F. Damilano-F.-D
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文献类型：
--
作者：
Bernhard W. Unsöld;Axel Kaul;Mauro Sbroggió;Carola Schubert;V. Regitz-Zagrosek;M. Brancaccio;F. Damilano-F.-D
目的Melusin是一种肌肉特异性伴侣蛋白，其表达是对压力超负荷的代偿性肥大反应所必需的。在此，我们采用综合性多中心方法评估了melusin过度表达在心肌梗死（MI）背景下的后果。方法和结果将在心脏中过表达melusin的小鼠（TG）和野生型对照（WT）进行永久性LAD结扎，并检查急性反应（第3天）和随后的重塑（2周）。野生型小鼠的死亡率在第3天和第7天之间是显著的，主要是由于心脏破裂，但是melusin的过表达强烈降低了死亡率（野生型中43.2%对melusin-TG中27.3%，P = 0.005）。在MI后第3天，即死亡高峰前的时间点，TG心脏热休克蛋白70表达增加，ERK 1/2信号转导增加，心肌细胞过度收缩和炎性细胞浸润减少，梗死区基质细胞蛋白表达增加。在MI后2周，melusin过表达赋予了有利的适应性重塑，其特征在于在存在相当程度的肥大的情况下减少左心室扩张和更好地保持收缩性。melusin TG小鼠的适应性重构的特征在于细胞凋亡和纤维化减少以及心肌细胞收缩力增加。结论：与其作为伴侣蛋白的功能一致，melusin过表达在MI后发挥双重保护作用，减少一系列适应不良过程。在MI后的早期阶段，减少炎症和肌细胞重塑可防止心脏破裂。慢性地，减少的肌细胞损失和基质重塑，以及保留的肌细胞收缩性，赋予适应性LV重塑。
AIMS Melusin is a muscle-specific chaperone protein whose expression is required for a compensatory hypertrophy response to pressure overload. Here, we evaluated the consequences of melusin overexpression in the setting of myocardial infarction (MI) using a comprehensive multicentre approach. METHODS AND RESULTS Mice overexpressing melusin in the heart (TG) and wild-type controls (WT) were subjected to permanent LAD ligation and both the acute response (Day 3) and subsequent remodelling (2 weeks) were examined. Mortality in wild-type mice was significant between Days 3 and 7, primarily due to cardiac rupture, but melusin's overexpression strongly reduced mortality (43.2% in wild-type vs. 27.3% in melusin-TG, P = 0.005). At Day 3 after MI, a time point preceding the mortality peak, TG hearts had increased heat shock protein 70 expression, increased ERK1/2 signalling, reduced cardiomyocyte hyper-contractility and inflammatory cell infiltrates, and increased matricellular protein expression in the infarcted area. At 2 weeks after MI, melusin overexpression conferred a favourable adaptive remodelling characterized by reduced left ventricle dilatation and better preserved contractility in the presence of a comparable degree of hypertrophy. Adaptive remodelling in melusin TG mice was characterized by reduced apoptosis and fibrosis as well as increased cardiomyocyte contractility. CONCLUSIONS Consistent with its function as a chaperone protein, melusin overexpression exerts a dual protective action following MI reducing an array of maladaptive processes. In the early phase after MI, reduced inflammation and myocyte remodelling protect against cardiac rupture. Chronically, reduced myocyte loss and matrix remodelling, with preserved myocyte contractility, confer adaptive LV remodelling.