Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy
Chronic akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: role of autophagy
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DOI：
10.1007/s00395-011-0222-8
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发表时间：
2011-11-01
影响因子：
9.5
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Hua, Yinan;Zhang, Yingmei;Ren, Jun
衰老通常伴随着心脏的几何和功能变化，尽管潜在的机制尚不清楚。最近的证据描述了Akt和自噬在衰老相关器官退化中的潜在作用。本研究旨在研究心脏特异性Akt激活对衰老诱导的心脏几何和功能变化的影响及其潜在机制。使用超声心动图、边缘检测和fura-2技术评估心脏几何形状、收缩和细胞内Ca2+特性。western blot检测胰岛素信号和自噬水平。我们的研究结果显示，与幼龄（3-4个月）小鼠相比，老年（24-26个月）小鼠的心脏肥大（室大小、壁厚、心肌细胞横截面面积增大）、纤维化、心脏收缩力下降、延长的再延长以及细胞内Ca2+释放和清除受损，这些影响被慢性Akt激活所加剧。衰老增强了Akt和mTOR的磷酸化，同时降低了PTEN、AMPK和ACC的磷酸化，且在Akt转基因小鼠中反应更为明显。GSK3 β磷酸化和eNOS水平不受衰老或Akt过表达的影响。衰老心脏beclin-1、Atg5和LC3-II-to-LC3-I比值降低，除Atg5外，Akt过度激活加剧了这种作用。老年小鼠p62水平显著升高，Akt水平升高更为明显。衰老和Akt均未改变β -葡糖醛酸酶活性和组织蛋白酶B，但衰老降低了LAMP1水平。此外，雷帕霉素减少衰老诱导的心肌细胞收缩和细胞内Ca2+功能障碍，而Akt激活抑制年轻而非衰老心肌细胞的自噬。综上所述，我们的数据表明Akt可能通过丧失自噬调节而加剧衰老诱导的心脏几何和收缩缺陷。
Aging is often accompanied with geometric and functional changes in the heart, although the underlying mechanisms remain unclear. Recent evidence has described a potential role of Akt and autophagy in aging-associated organ deterioration. This study was to examine the impact of cardiac-specific Akt activation on aging-induced cardiac geometric and functional changes and underlying mechanisms involved. Cardiac geometry, contractile and intracellular Ca2+ properties were evaluated using echocardiography, edge-detection and fura-2 techniques. Level of insulin signaling and autophagy was evaluated by western blot. Our results revealed cardiac hypertrophy (enlarged chamber size, wall thickness, myocyte cross-sectional area), fibrosis, decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca2+ release and clearance in aged (24-26 month-old) mice compared with young (3-4 month-old) mice, the effects of which were accentuated by chronic Akt activation. Aging enhanced Akt and mTOR phosphorylation while reducing that of PTEN, AMPK and ACC with a more pronounced response in Akt transgenic mice. GSK3 beta phosphorylation and eNOS levels were unaffected by aging or Akt overexpression. Levels of beclin-1, Atg5 and LC3-II-to-LC3-I ratio were decreased in aged hearts, the effect of which with the exception of Atg 5 was exacerbated by Akt overactivation. Levels of p62 were significantly enhanced in aged mice with a more pronounced increase in Akt mice. Neither aging nor Akt altered beta-glucuronidase activity and cathepsin B although aging reduced LAMP1 level. In addition, rapamycin reduced aging-induced cardiomyocyte contractile and intracellular Ca2+ dysfunction while Akt activation suppressed autophagy in young but not aged cardiomyocytes. In conclusion, our data suggest that Akt may accentuate aging-induced cardiac geometric and contractile defects through a loss of autophagic regulation.