Activation of PI3K gamma/Akt pathway increases cardiomyocyte HMGB1 expression in diabetic environment

作者：Song, Jia; Liu, Qian; Tang, Han; Tao, Aibin; Wang, Hao; Kao, Raymond; Rui, Tao^*

来源：Oncotarget, 2016, 7(49): 80803-80810.

DOI：10.18632/oncotarget.13096

• cardiomyocyte
• HMGB1
• PI3K gamma
• Akt
• diabetes mellitus

Background: The high mobility group box 1 (HMGB1) protein mediates the cardiomyocyte-cardiac fibroblast interaction that contributes to induction of myocardial fibrosis in diabetes mellitus (DM). In the present study, we aim to investigate the intracellular signaling pathway that leads to cardiomyocyte HMGB1 expression under a diabetic environment.
Results: HMGB1 expression is increased in high concentration of glucose (HG)-conditioned cardiomyocytes. Challenging cardiomyocytes with HG also increased PI3K gamma and Akt phosphorylation. Inhibition ofPI3K gamma (CRISPR/Cas9 knockout plasmid or AS605240) prevented HG-induced Akt phosphorylation and HMGB1 expression by the cardiomyocytes. In addition, inhibition of Akt (Akt1/2/3 siRNA or A6730) attenuated HG-induced HMGB1 production. Finally, challenging cardiomyocytes with HG resulted in increased reactive oxygen species (ROS) production. Treatment of cardiomyocytes with an antioxidant (Mitotempo) abolished HG-induced PI3K. and Akt activation, as well as HMGB1 production.
Materials and Methods: Isolated rat cardiomyocytes were cultured with a high concentration of glucose. Cardiomyocyte phosphatidylinositol 3-kinase gamma (PI3K gamma) and Akt activation were determined by Western blot. Cardiomyocyte HMGB1 production was evaluated with Western blot and enzyme-linked immunosorbent assay (ELISA), while cardiomyocyte oxidative stress was determined with a DCFDA fluorescence probe.
Conclusions: Our results suggest that the cardiomyocytes incur an oxidative stress under diabetic condition, which subsequently activates the PI3K gamma/Akt cell-signaling pathway and further increases HMGB1 expression.

• 出版日期2016-12-6
• 单位江苏大学