Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice.
Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice.
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DOI：
10.1253/circj.71.1958
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发表时间：
2007-11
期刊：
影响因子：
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通讯作者：
R. Yamamoto;H. Akazawa;K. Ito;H. Toko;Masanori Sano;N. Yasuda;Yingjie Qin;Yoko Kudo;T. Sugaya;K. Chien;I. Komuro
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文献类型：
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作者：
R. Yamamoto;H. Akazawa;K. Ito;H. Toko;Masanori Sano;N. Yasuda;Yingjie Qin;Yoko Kudo;T. Sugaya;K. Chien;I. Komuro
背景血管紧张素II(AT)参与心脏重塑，导致心力衰竭，AT1受体的药物抑制可提高心力衰竭患者的死亡率和发病率。本研究的目的是阐明AT1受体在肌肉LIM蛋白(MLP)缺陷小鼠疾病进展中的作用，这些小鼠由于心肌细胞机械感受器的功能缺陷而容易发生心力衰竭。方法与结果分析了MLP基因敲除(MLPKO)小鼠和MLP-AT1a受体双基因敲除(DKO)小鼠的心脏。MLPKO心脏表现出明显的心腔扩张，伴有心肌纤维化和胎儿基因程序的重新激活。所有这些变化在DKO患者的心脏中都明显较轻。DKO患者左心室(LV)收缩功能和充盈功能受损程度减轻。然而，DKO心脏肌浆网钙-ATPase 2的松弛功能受损和表达下调未见明显改变。结论AT1a受体参与了MLPKO小鼠心脏重构和心功能恶化的进程。这些结果表明，阻断该受体在防止扩张型心肌病心衰进展方面是有效的。
BACKGROUND Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbidity in patients of heart failure. The aim of this study was to elucidate the role of the AT1 receptor in disease progression in muscle LIM protein (MLP)-deficient mice, which are susceptible to heart failure because of defective function of mechanosensors in cardiomyocytes. METHOD AND RESULTS Hearts from MLP knockout (MLPKO) mice and MLP-AT1a receptor double knockout (DKO) mice were analyzed. MLPKO hearts showed marked chamber dilatation with cardiac fibrosis and reactivation of the fetal gene program. All of these changes were significantly milder in the DKO hearts. Impaired left ventricular (LV) contractility and filling were alleviated in DKO hearts. However, the impaired relaxation and downregulated expression of sarcoplasmic reticulum calcium-ATPase 2 were unchanged in DKO hearts. CONCLUSIONS The AT1a receptor is involved in progression of LV remodeling and deterioration of cardiac function in the hearts of MLPKO mice. These results suggest that blockade of the receptor is effective in preventing progression of heart failure in dilated cardiomyopathy.