KAIST. Korea: A
KAIST research team has identified the fundamental
principle in deciding the fate of cardiomyocyte or heart muscle cells.
They have determined that it depends on the degree of stimulus in β-adrenergic receptor signal transduction pathway in the cardiomyocyte to control cells' survival or death. The findings, the team hopes, can be used to treat various heart diseases including heart failure.
The research was
led by KAIST Department of Bio and Brain Engineering Chair Professor Kwang-Hyun
Cho and conducted by Dr. Sung-Young Shin (lead author) and Ph.D.
candidates Ho-Sung Lee and Joon-Hyuk Kang. The research was conducted jointly with GIST
(Gwangju Institute of Science and Technology) Department of Biological Sciences
Professor Do-Han Kim’s team. The research was supported by the Ministry of
Science, ICT and Future Planning, Republic of Korea, and the National Research
Foundation of Korea. The paper was published in Nature Communications on December 17, 2014 with the title, “The switching role of β-adrenergic receptor
signalling in cell survival or death decision of cardiomyocytes.”
The β-adrenergic
receptor signal transduction pathway can
promote cell survival (mediated by β2 receptors), but also can result
in cell death by inducing toxin (mediated by β1
receptors) that leads to various heart diseases including heart failure.
Past attempts to identify the fundamental principle in the fate
determining process of cardiomyocyte based on β-adrenergic receptor signalling concluded without much success.
The β-adrenergic
receptor is a type of protein on the
cell membrane of cardiomyocyte (heart muscle cell) that when stimulated by neurohormones
such as epinephrine or norepinephrine would transduce signals making the cardiomyocyte
contract faster and stronger.
The research team used large-scale computer simulation analysis
and systems biology to identify ERK* and ICER** signal transduction pathways
mediated by a feed-forward circuit as a key molecular switch that decides
between cell survival and death.
Weak β-adrenergic receptor stimulations activate ERK signal transduction pathway,
increasing Bcl-2*** protein expression to promote cardiomyocyte survival. On the
other hand, strong β-adrenergic
receptor stimulations activate ICER
signal transduction pathway, reducing Bcl-2 protein expression to promote cardiomyocyte
death.
Researchers used a systems biology approach to identify the mechanism of B-blocker****, a common drug prescribed for heart failure. When cardiomyocyte is treated with β1 inhibitor, strong stimulation on β-adrenergic receptor increases Bcl-2 expression, improving the chance of cardiomyocyte survival, a cell protection effect.
Professor
Kwang-Hyun Cho said, “This research used systems biology, an integrated,
convergence research of IT (information technology) and BT (biotechnology), to
successfully identify the mechanism in deciding the fate of cardiomyocytes
based on the β-adrenergic
receptor signal transduction pathway for
the first time. I am hopeful that this research will enable the control of
cardiomyocyte survival and death to treat various heart diseases including
heart failure.”
Professor
Cho’s
team was the first to pioneer a new field of systems biology, especially
concerning
the complex signal transduction network involved in diseases. Their
research is
focused on modelling, analyzing simulations, and experimentally proving
signal pathways. Professor Cho has published 140 articles in
international journals
including Cell, Science, and Nature.
* ERK (Extracellular
signal-regulated kinases): Signal
transduction molecule involved in cell survival
** ICER (Inducible
cAMP early repressor): Signal
transduction molecule involved in cell death
*** Bcl-2 (B-cell
lymphoma 2): Key signal transduction molecule
involved in promotion of cell survival
**** β-blocker: Drug that acts as β-adrenergic receptor
inhibitor known to slow the progression of heart failure, hence used most
commonly in medicine.