科研之友
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摘要
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 (beta AR) 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 forskolm 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 beta AR blocker propranolol In agreement with previous results demonstrating increased fatty acid oxidation rates in akt2(-/-) myocardium we found increased peroxisome proliferator-activated receptor alpha (PPAR alpha) activity in the hearts of these animals Interestingly increased myocardial Rab4a expression was present in mice with cardiac-specific overexpression of PPAR alpha and was also observed upon stimulation of PPAR alpha activity in cultured cardiomyocytes Accordingly propranolol attenuated the development of cardiac hypertrophy in the PPAR alpha transgenic mice as well Our results indicate that reduced Akt2 leads to up regulation of Rab4a expression in cardiomyocytes in a cell autonomous fashion
- 出版日期2010-12
