UCSD: Researchers at the University of California, San Diego School of
Medicine have identified a key piece in the complex molecular puzzle
underlying heart failure – a serious and sometimes life-threatening
disorder affecting more than 5 million Americans.
In a study published in the March 5 online issue of Cell Reports,
Xiang-Dong Fu, PhD, and colleagues explored the heart’s progression
from initial weakening to heart failure, and found that a protein, known
as RBFox2, plays a critical role in this process.
Contrary to its name, heart failure does not mean the heart
completely stops working, but rather that the heart muscle becomes
weakened to the point that it can no longer pump enough blood for the
body’s needs. Coronary artery disease, high blood pressure and heart
defects are among various factors that can lead to heart failure, which
has no cure and is currently treated with medications, lifestyle
changes, oxygen and cardiac devices. In some cases, a heart transplant
is required.
Fu and his team studied the cellular changes that occur during the
weakened heart muscle’s transition from working harder to maintain
proper blood flow, known as the compensatory stage, to failing to
sustain adequate blood supplies, known as decompensation. “Numerous
signaling molecules have been shown to be part of the compensatory
program, but relatively little was known about the transition to
decompensation that leads to heart failure,” said Fu.
To answer this question, the research team explored RBFox2, a gene
splicing protein known to be involved in the heart’s early development
and ongoing function. “We wanted to know how RBFox2 might contribute to
decompensation, given its vital role in heart functions,’’ said Fu.
In their studies, the researchers restricted blood flow in mice to
induce a condition similar to heart failure and then tested their RBFox2
protein levels over a period of weeks. “Strikingly, we found that
RBfox2 protein was largely diminished in the hearts of live mice five
weeks after the procedure,” he said.
Fu and colleagues also tested the reduction of the RBFox2 protein in
mice specially-engineered to lack the protein. In these experiments, the
mice lacking the RBFox 2 protein developed heart failure symptoms
similar to those in the blood-restricted mice, suggesting a functional
connection between the reduction of RBFox2 and decline of the heart
muscle.
The research team then sought to determine why, from a mechanistic
point of view, the loss of RBFox2 would weaken the heart. To study this,
they examined RBFox2-controlled changes in gene expression, which
refers to the biological actions taken by genes, during various
scenarios of heart development in mice. Specifically, the scientists
compared changes detected in the hearts of RBFox2-deleted or
blood-restricted mice to those that occur during post-natal heart
“remodeling.” Remodeling is the process of heart strengthening that
begins at birth and continues throughout childhood. “The RBFox2
deletion-induced genetic changes are similar to those that occurred
during blood restriction-induced heart failure, but opposite to those
taking place during heart remodeling,” said Fu. “This indicates that the
normal developmental program for strengthening heart performance is
reversed during heart failure.”
Fu said the finding could lead to new drug targets for heart failure.
“We’ve learned that the RBFox2 protein is very important in keeping
the heart muscle strong,” he said. “Our research shows its diminished
expression coincides with the weakening of the heart muscle. This
strongly suggests a causal role for this protein in heart failure. By
understanding these mechanisms, we may be able to find a way to prevent
the decreased expression of RBFox2, which may help in preventing heart
failure.”
Co-authors include Chaoliang Wei, Jinsong Qiu, Yu Zhou, Yuanchao Xue,
Jing Hu, Kunfu Ouyang, Indroneal Banerjee, Hairi Li, Ju Chen, all at UC
San Diego; and Caimei Zhang, Biyi Chen and Long-Sheng Song, all at the
University of Iowa Carver College of Medicine.
Funding for this research came, in part, from the National Institutes of Health (grants GM049369, HG004659, and HG007005).