Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy.
Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy.
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DOI：
10.2337/db09-1456
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发表时间：
2010-06
期刊：
影响因子：
7.7
通讯作者：
Ritchie RH
中科院分区：
文献类型：
--
作者：
Huynh K;McMullen JR;Julius TL;Tan JW;Love JE;Cemerlang N;Kiriazis H;Du XJ;Ritchie RH
令人信服的流行病学和临床证据已经确定了一种特殊的糖尿病心肌病，其特征是早期舒张期功能障碍和不利的结构重构。胰岛素样生长因子1(IGF-1)受体(IGF-1R)的激活促进生理性心脏生长和增强收缩功能。本研究的目的是研究心脏特异性IGF-1R的过度表达是否能预防糖尿病引起的心肌重构和糖尿病小鼠模型相关的功能障碍。用链脲佐菌素诱导7周龄雄性IGF-1R转基因小鼠发生1型糖尿病，并跟踪观察8周。除心导管术外，分别使用多普勒和M型超声心动图评估舒张期和收缩期功能。心肌纤维化和心肌细胞宽度、心脏重量指数、基因表达、Akt活性和IGF-1R蛋白含量也被评估。与非糖尿病小鼠相比，非转基因(NTG)糖尿病小鼠的多普勒超声心动图上的初始(E)与秒(A)血流速度比(E：A比率)降低，减速时间延长，这是舒张期功能障碍的指示标志。与非糖尿病组相比，糖尿病组心肌细胞宽度、胶原沉积、促肥大和促纤维化基因表达也增加。转基因IGF-1R的过表达显著减少了胶原沉积，并伴随着舒张期功能障碍发生率的降低。与非糖尿病小鼠相比，胰岛素样生长因子-1R非糖尿病小鼠的∼蛋白酪氨酸氨基转移酶磷酸化水平增加了15倍，并且这种情况在糖尿病小鼠中保持不变。目前的研究表明，心脏IGF-1R的过度表达可以预防糖尿病引起的心脏纤维化和舒张期功能障碍。靶向IGF-1R-Akt信号转导通路可能成为治疗糖尿病心脏病的靶点。
Compelling epidemiological and clinical evidence has identified a specific cardiomyopathy in diabetes, characterized by early diastolic dysfunction and adverse structural remodeling. Activation of the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) promotes physiological cardiac growth and enhances contractile function. The aim of the present study was to examine whether cardiac-specific overexpression of IGF-1R prevents diabetes-induced myocardial remodeling and dysfunction associated with a murine model of diabetes. Type 1 diabetes was induced in 7-week-old male IGF-1R transgenic mice using streptozotocin and followed for 8 weeks. Diastolic and systolic function was assessed using Doppler and M-mode echocardiography, respectively, in addition to cardiac catheterization. Cardiac fibrosis and cardiomyocyte width, heart weight index, gene expression, Akt activity, and IGF-1R protein content were also assessed. Nontransgenic (Ntg) diabetic mice had reduced initial (E)-to-second (A) blood flow velocity ratio (E:A ratio) and prolonged deceleration times on Doppler echocardiography compared with nondiabetic counterparts, indicative markers of diastolic dysfunction. Diabetes also increased cardiomyocyte width, collagen deposition, and prohypertrophic and profibrotic gene expression compared with Ntg nondiabetic littermates. Overexpression of the IGF-1R transgene markedly reduced collagen deposition, accompanied by a reduction in the incidence of diastolic dysfunction. Akt phosphorylation was elevated ∼15-fold in IGF-1R nondiabetic mice compared with Ntg, and this was maintained in a setting of diabetes. The current study suggests that cardiac overexpression of IGF-1R prevented diabetes-induced cardiac fibrosis and diastolic dysfunction. Targeting IGF-1R–Akt signaling may represent a therapeutic target for the treatment of diabetic cardiac disease.
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DOI：
10.1152/ajpheart.01200.2004
发表时间：
2005-10-01
影响因子：
4.8
作者：
Malhotra, A;Begley, R;Meggs, LG
通讯作者：
Meggs, LG
DOI：
10.1152/ajpheart.00427.2006
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2006-11-01
影响因子：
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9.3
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DOI：
10.1073/pnas.93.16.8630
发表时间：
1996-08-06
影响因子：
11.1
作者：
Reiss, K;Cheng, W;Anversa, P
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Anversa, P
影响因子：
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