Chronic Akt blockade aggravates pathological hypertrophy and inhibits physiological hypertrophy

Chronic Akt blockade aggravates pathological hypertrophy and inhibits physiological hypertrophy

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...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology Vol. 302; no. 2; p. H420
Main Authors: Buss, Sebastian J, Riffel, Johannes H, Malekar, Pratima, Hagenmueller, Marco, Asel, Christina, Zhang, Min, Weiss, Celine, Katus, Hugo A, Hardt, Stefan E
Format: Journal Article
Language:English
Published: United States 01-01-2012
Subjects:
Animals
Cardiomegaly - metabolism
Cardiomegaly - pathology
Cardiomegaly, Exercise-Induced - physiology
Enzyme Inhibitors - pharmacology
Male
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Phosphorylation - drug effects
Physical Conditioning, Animal - physiology
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Rats
Rats, Wistar
Rotenone - analogs & derivatives
Rotenone - pharmacology
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Summary: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.
ISSN:1522-1539
DOI:10.1152/ajpheart.00211.2011