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Publication : Akt2 deficiency promotes cardiac induction of Rab4a and myocardial β-adrenergic hypersensitivity.

First Author  Etzion S Year  2010
Journal  J Mol Cell Cardiol Volume  49
Issue  6 Pages  931-40
PubMed ID  20728450 Mgi Jnum  J:267301
Mgi Id  MGI:6258626 Doi  10.1016/j.yjmcc.2010.08.011
Citation  Etzion S, et al. (2010) Akt2 deficiency promotes cardiac induction of Rab4a and myocardial beta-adrenergic hypersensitivity. J Mol Cell Cardiol 49(6):931-40
abstractText  Patients with diabetes mellitus can develop cardiac dysfunction in the absence of underlying coronary artery disease or hypertension; a condition defined as diabetic cardiomyopathy. Mice lacking the intracellular protein kinase Akt2 develop a syndrome that is similar to diabetes mellitus type 2. Expression profiling of akt2(-/-) myocardium revealed that Rab4a, a GTPase involved in glucose transporter 4 translocation and beta-adrenergic receptor (betaAR) recycling to the plasma membrane, was significantly induced. We therefore hypothesized that Akt2 deficiency increases myocardial beta-adrenergic sensitivity. Confirmatory analysis revealed up-regulation of Rab4a mRNA and protein in akt2(-/-) myocardium. In cultured cardiomyocyte experiments, Rab4a was induced by pharmacological inhibition of Akt as well as by specific knockdown of Akt2 with siRNA. Isolated akt2(-/-) hearts were hypersensitive to isoproterenol (ISO) but exhibited normal sensitivity to forskolin. Prolonged ISO treatment led to increased cardiac hypertrophy in akt2(-/-) mice compared to wild type mice. In addition, spontaneous hypertrophy was noted in aged akt2(-/-) hearts that was inhibited by treatment with the betaAR blocker propranolol. In agreement with previous results demonstrating increased fatty acid oxidation rates in akt2(-/-) myocardium, we found increased peroxisome proliferator-activated receptor alpha (PPARalpha) activity in the hearts of these animals. Interestingly, increased myocardial Rab4a expression was present in mice with cardiac-specific overexpression of PPARalpha and was also observed upon stimulation of PPARalpha activity in cultured cardiomyocytes. Accordingly, propranolol attenuated the development of cardiac hypertrophy in the PPARalpha transgenic mice as well. Our results indicate that reduced Akt2 leads to up-regulation of Rab4a expression in cardiomyocytes in a cell-autonomous fashion that may involve activation of PPARalpha. This maladaptive response is associated with hypersensitivity of akt2(-/-) myocardium to beta-adrenergic stimulation.
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