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GW24-e2121 Adenosine monophosphate-activated protein kinase attenuates cardiomyocyte hypertrophy through regulation of FOXO3a/MAFbx signalling pathway
  1. Chen BaoLin1,
  2. Baolin Chen1,
  3. Zhaojun Xiong2,
  4. Yuedong Ma3,
  5. Rongsen Meng3,
  6. Chengxi Zhang2,
  7. Guangqin Chen3,
  8. Chen Liu3,
  9. Yugang Dong3
  1. 1Department of Cardiology, The People’s Hospital of Guizhou Province, Guiyang, China
  2. 2Department of Cardiology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
  3. 3Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

Abstract

Objectives To examine the inhibitory effects of adenosine monophosphate-activated protein kinase (AMPK) activation on cardiomyocyte hypertrophy in vitro and to investigate the underlying molecular mechanisms.

Methods Cultured neonatal rat cardiomyocytes were treated with the specific AMPK activator 5-aminoimidazole-4-carboxamide ribonu-cleoside (AICAR, 0.5 mmol/L) and the specific AMPK antagonist Compound C (1 μmol/L), and then stimulated with angiotensin II (Ang II, 1 μmol/L). The Muscle atrophy F-box (MAFbx)-small interfering RNA (siRNA) was transfected into cardiomyocytes using Lipofectamine 2000. The surface area of cultured cardiomyocytes was measured using planimetry. The protein degradation was determined using high performance liquid chromatogra-phy (HPLC). The expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), MAFbx, as well as the phosphorylation levels of AMPK and Forkhead box O 3a (FOXO3a), were separately measured using Western blot or real-time polymerase chain reaction.

Results Activation of AMPK by AICAR inhibited Ang II-induced increase in cardiomyocyte area (P < 0.01 vs Ang II group), ANP and BNP protein expression (P < 0.01 vs Ang II group), as well as Ang II-induced decrease in protein degradation (P < 0.01 vs Ang II group). Compared with the control group, Ang II treatment significantly increased the p-FOXO3a level, whereas down-regulated MAFbx mRNA and protein expression levels in cultured cardiomyocytes (P < 0.01). Furthermore, AMPK activation decreased the p-FOXO3a level, increased the activity of transcription factor FOXO3a and up-regulated downstream atrogene MAFbx mRNA and protein expression (P < 0.05 vs Ang II group). Treatment of hypertrophied cardiomyocytes with Compound C blocked the effects of AMPK on cardiomyocyte hypertrophy and changes to the FOXO3a/MAFbx pathway (P < 0.05 vs Ang II + AICAR group). The effects of AICAR on cardiomyocyte hypertrophy were also blunted after MAFbx was silenced by transfection of cardiomyocytes with MAFbx-siRNA (P < 0.01 vs Ang II + AICAR group).

Conclusions The present study demonstrates that AMPK activation inhibits cardiomyocyte hypertrophy by modulating the atrophy-related FOXO3a/MAFbx signaling pathway in vitro.

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