Cardiac overexpression of insulin-like growth factor 1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction but not hypertrophy: Roles of Akt, mTOR, GSK3beta, and PTEN.
Cardiac overexpression of insulin-like growth factor 1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction but not hypertrophy: Roles of Akt, mTOR, GSK3beta, and PTEN.
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DOI：
10.1016/j.freeradbiomed.2010.07.020
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发表时间：
2010-10-15
影响因子：
7.4
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Zhang, Bingfang;Turdi, Subat;Li, Quan;Lopez, Faye L.;Eason, Anna R.;Anversa, Piero;Ren, Jun
关键词：
长期饮酒会导致酒精性心肌病的发生，表现为心肌肥大和收缩功能障碍。本研究旨在探讨胰岛素样生长因子I(IGF-1)转基因过表达对酒精性心脏收缩功能障碍的影响。野生型FVB和心脏特异性IGF-1小鼠被置于4%酒精或对照饮食中16周。通过超声心动图、心肌细胞和细胞内钙离子特性评价心脏几何构型和机械功能。分别用Masson三色染色和TUNEL法检测心肌纤维化和细胞凋亡的组织学变化。免疫印迹法检测铜/锌超氧化物歧化酶、钙离子调控蛋白、生存关键信号分子Akt、mTor、Gsk3β、Foxo3a和第10号染色体上的Akt磷酸酶和张力蛋白同源物的负调控蛋白以及线粒体蛋白UCP-2和Pgc1α的表达和/或磷酸化。慢性酒精摄入可导致心肌肥大、间质纤维化、线粒体数量减少、心肌收缩功能和细胞内钙处理能力下降、SOD1表达降低、超氧化物歧化产物生成增加和明显的细胞凋亡，除心肌肥厚外，所有这些都被转基因IGF-1消除。免疫印迹结果显示，饮酒后Akt、mTor、Gsk3β和Foxo3a的磷酸化水平降低，Foxo3a和PTEN上调，SERCA2a、Pgc1α和Ucp-2的表达受到抑制。所有这些酒精引起的存活和线粒体蛋白的改变都被IGF-1缓解。综上所述，这些数据有利于IGF-1在酒精诱导的心肌收缩功能障碍中发挥有益的作用，而不依赖于心肌肥厚。
Chronic alcohol intake leads to the development of alcoholic cardiomyopathy manifested by cardiac hypertrophy and contractile dysfunction. This study was designed to examine the effect of transgenic overexpression of insulin-like growth factor I (IGF-1) on alcohol-induced cardiac contractile dysfunction. Wild-type FVB and cardiac-specific IGF-1 mice were placed on a 4% alcohol or control diet for 16 weeks. Cardiac geometry and mechanical function were evaluated by echocardiography, cardiomyocyte and intracellular Ca2+ properties. Histological analyses for cardiac fibrosis and apoptosis were evaluated by Masson trichrome staining and TUNEL assay, respectively. Expression and/or phosphorylation of Cu/Zn superoxide dismutase (SOD1), Ca2+ handling proteins, key signaling molecules for survival including Akt, mTOR, GSK3β, Foxo3a and the negative regulator of Akt phosphatase and tensin homolog on chromosome ten (PTEN) as well as mitochondrial proteins UCP-2 and PGC1α were evaluated by western blot analysis. Chronic alcohol intake led to cardiac hypertrophy, interstitial fibrosis, reduced mitochondrial number, compromised cardiac contractile function and intracellular Ca2+ handling, decreased SOD1 expression, elevated superoxide production and overt apoptosis, all of which with the exception of cardiac hypertrophy were abrogated by the IGF-1 transgene. Immunoblotting data showed reduced phosphorylation of Akt, mTOR, GSK3β and Foxo3a, upregulated Foxo3a and PTEN, as well as dampened SERCA2a, PGC1α and UCP-2 following alcohol intake. All these alcohol-induced changes in survival and mitochondrial proteins were alleviated by IGF-1. Taken together, these data favor a beneficial role of IGF-1 in alcohol-induced myocardial contractile dysfunction independent of cardiac hypertrophy.
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影响因子：
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