Research Papers:

Activation of PI3Kγ/Akt pathway increases cardiomyocyte HMGB1 expression in diabetic environment

Jia Song, Qian Liu, Han Tang, Aibin Tao, Hao Wang, Raymond Kao and Tao Rui _

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Oncotarget. 2016; 7:80803-80810. https://doi.org/10.18632/oncotarget.13096

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Jia Song1, Qian Liu1, Han Tang1, Aibin Tao1,2, Hao Wang1, Raymond Kao2, Tao Rui1,2,3

1Division of Cardiology, Department of Medicine, The Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212002, China

2Critical Illness Research, Lawson Health Research Institute, London, Ontario, N6A 4G5, Canada

3Departments of Medicine, Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, N6A 4G5, Canada

Correspondence to:

Tao Rui, email: [email protected]

Keywords: cardiomyocyte, HMGB1, PI3Kγ, Akt, diabetes mellitus

Received: August 29, 2016     Accepted: October 28, 2016     Published: November 04, 2016


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 PI3Kγ and Akt phosphorylation. Inhibition of PI3Kγ (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 PI3Kγ 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 (PI3Kγ) 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 PI3Kγ/Akt cell-signaling pathway and further increases HMGB1 expression.

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