Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.
Am J Physiol Heart Circ Physiol. 2012 Jan;302(2):H420-30. doi: 10.1152/ajpheart.00211.2011. Epub 2011 Nov 4.
The attenuation of adverse myocardial remodeling and pathological left ventricular (LV) hypertrophy is one of the hallmarks for improving the prognosis after myocardial infarction (MI). The protein kinase Akt plays a central role in regulating cardiac hypertrophy, but the in vivo effects of chronic pharmacological inhibition of Akt are unknown. We investigated the effect of chronic Akt blockade with deguelin on the development of pathological [MI and aortic banding (AB)] and physiological (controlled treadmill running) hypertrophy. Primary cardiomyocyte cultures were incubated with 10 μmol deguelin for 48 h, and Wistar rats were treated orally with deguelin (4.0 mg·kg(-1)·day(-1)) for 4 wk starting 1 day after the induction of MI or AB. Exercise-trained animals received deguelin for 4 wk during the training period. In vitro, we observed reduced phosphorylation of Akt and glycogen synthase kinase (GSK)-3β after an incubation with deguelin, whereas MAPK signaling was not significantly affected. In vivo, treatment with deguelin led to attenuated phosphorylation of Akt and GSK-3β 4 wk after MI. These animals showed significantly increased heart weights and impaired LV function with increased end-diastolic diameters (12.0 ± 0.3 vs. 11.1 ± 0.3 mm, P < 0.05), end-diastolic volumes (439 ± 8 vs. 388 ± 18 μl, P < 0.05), and cardiomyocyte sizes (+20%, P < 0.05) compared with MI animals receiving vehicle treatment. Furthermore, activation of Ca(2+)/calmodulin-dependent kinase II in deguelin-treated MI animals was increased compared with the vehicle-treated group. Four wk after AB, we observed an augmentation of pathological hypertrophy in the deguelin-treated group with a significant increase in heart weights and cardiomyocyte sizes (>20%, P < 0.05). In contrast, the development of physiological hypertrophy was inhibited by deguelin treatment in exercise-trained animals. In conclusion, chronic Akt blockade with deguelin aggravates adverse myocardial remodeling and antagonizes physiological hypertrophy.
抑制不良心肌重构和病理性左心室（LV）肥厚是改善心肌梗死（MI）后预后的标志之一。蛋白激酶 Akt 在调节心肌肥厚中起着核心作用，但慢性药理抑制 Akt 的体内作用尚不清楚。我们研究了用 deguelin 慢性抑制 Akt 对病理性（MI 和主动脉缩窄（AB））和生理性（控制跑步机跑步）肥大发展的影响。原代心肌细胞培养物用 10 μmol deguelin 孵育 48 h，Wistar 大鼠在 MI 或 AB 诱导后 1 天开始每天口服 deguelin（4.0 mg·kg(-1)·day(-1)）4 周。运动训练动物在训练期间接受 4 周的 deguelin 治疗。在体外，我们观察到孵育 deguelin 后 Akt 和糖原合酶激酶（GSK）-3β 的磷酸化减少，而 MAPK 信号未受到显著影响。在体内，deguelin 治疗导致 MI 后 4 周 Akt 和 GSK-3β 的磷酸化减弱。这些动物的心脏重量显著增加，LV 功能受损，舒张末期直径增加（12.0 ± 0.3 对 11.1 ± 0.3 mm，P < 0.05），舒张末期容积增加（439 ± 8 对 388 ± 18 μl，P < 0.05），心肌细胞大小增加（+20%，P < 0.05）与接受载体处理的 MI 动物相比。此外，与接受载体处理的组相比，deguelin 处理的 MI 动物中的 Ca(2+)/钙调蛋白依赖性激酶 II 激活增加。AB 后 4 周，我们观察到 deguelin 处理组的病理性肥大增加，心脏重量和心肌细胞大小显著增加（>20%，P < 0.05）。相比之下，在运动训练的动物中，deguelin 治疗抑制了生理性肥大的发展。总之，用 deguelin 慢性抑制 Akt 加重不良心肌重构并拮抗生理性肥大。
