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The Journal of Physiological Sciences

, Volume 68, Issue 4, pp 503–520 | Cite as

Investigating β-adrenergic-induced cardiac hypertrophy through computational approach: classical and non-classical pathways

  • Ali Khalilimeybodi
  • Alireza DaneshmehrEmail author
  • Babak Sharif-Kashani
Original Paper

Abstract

The chronic stimulation of β-adrenergic receptors plays a crucial role in cardiac hypertrophy and its progression to heart failure. In β-adrenergic signaling, in addition to the well-established classical pathway, Gs/AC/cAMP/PKA, activation of non-classical pathways such as Gi/PI3K/Akt/GSK3β and Gi/Ras/Raf/MEK/ERK contribute in cardiac hypertrophy. The signaling network of β-adrenergic-induced hypertrophy is very complex and not fully understood. So, we use a computational approach to investigate the dynamic response and contribution of β-adrenergic mediators in cardiac hypertrophy. The proposed computational model provides insights into the effects of β-adrenergic classical and non-classical pathways on the activity of hypertrophic transcription factors CREB and GATA4. The results illustrate that the model captures the dynamics of the main signaling mediators and reproduces the experimental observations well. The results also show that despite the low portion of β2 receptors out of total cardiac β-adrenergic receptors, their contribution in the activation of hypertrophic mediators and regulation of β-adrenergic-induced hypertrophy is noticeable and variations in β1/β2 receptors ratio greatly affect the ISO-induced hypertrophic response. The model results illustrate that GSK3β deactivation after β-adrenergic receptor stimulation has a major influence on CREB and GATA4 activation and consequent cardiac hypertrophy. Also, it is found through sensitivity analysis that PKB (Akt) activation has both pro-hypertrophic and anti-hypertrophic effects in β-adrenergic signaling.

Keywords

β-Adrenergic signaling Non-classical pathways Gi/PI3K/Akt/GSK3β pathway Gi/Ras/Raf/MEK/ERK pathway CREB transcription factor GATA4 transcription factor 

Notes

Acknowledgements

We convey our thanks to Dr. T. Jamali and Dr. M. Dehghani for their great help.

Compliance with ethical standards

Funding

There was no funding for this work.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

12576_2017_557_MOESM1_ESM.docx (330 kb)
Supplementary material 1 (DOCX 329 kb)

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Copyright information

© The Physiological Society of Japan and Springer Japan KK 2017

Authors and Affiliations

  • Ali Khalilimeybodi
    • 1
  • Alireza Daneshmehr
    • 1
    Email author
  • Babak Sharif-Kashani
    • 2
  1. 1.Department of Mechanical EngineeringCollege of Engineering, University of TehranTehranIran
  2. 2.Department of CardiologyMassih-Daneshvari Hospital, Shahid Beheshti University of Medical SciencesTehranIran

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