- Role transcription co-factors--proteins that are key to the regulation and expression of genes provide important clues into how heart failure develops.
- Cdk8 regulates the expression of thousands of genes and is part of the Mediator complex.
- Declining heart function and heart failure was indicated by an increase in Cdk8 levels.
- Modifying gene expression may provide a path to preventive treatments for heart failure.
Heart failure is a progressive disease that begins when the heart adapts to stressors--high blood pressure, coronary artery disease, or diabetes.
The heart muscle becomes weakened over time, making it increasingly difficult for the heart to pump blood through the body.
These stressors can lead to dilated cardiomyopathy, in which the heart's left ventricle (pumping chamber) stretches, enlarges, and becomes thinner.
During myopathy there are changes in gene expression, but it remains unclear whether these changes are due to declining heart function or whether these changes are part of the progression to heart failure.
Mediator Complex regulate Gene Expression in Heart Muscles
A better understanding of the co-factors--proteins that are key to the regulation and expression of genes could provide important clues into how heart failure develops.
In a new study, University of Iowa Health Care researchers report on the role of a protein--part of a large group of transcription co-factors called the Mediator complex--in regulating gene expression in heart muscle cells.
"A key question is how does the heart go from a normal state to a failing one after undergoing stress in some manner?" says Duane Hall, lead author of the study. "A lot of labs are trying to understand how that progression occurs."
"It's known that many genes are expressed during heart failure that are representative of a developing heart, so in these instances the heart may be trying to re-install developmental programs in order to adapt to those pressures," adds Chad Grueter, assistant professor of internal medicine in the UI Carver College of Medicine and senior author of the study.
Transcriptional gene regulation happens, looking at how gene expression occurs through this Mediator complex could reveal the reason.
Heart tissue samples from patients with heart failure was examined and the levels of the protein Cdk8 in heart muscle cells were elevated.
Cdk8 regulates the expression of thousands of genes and is part of the Mediator complex. The researchers over-expressed the protein in mouse heart cells. Declining heart function and heart failure was indicated by an increase in Cdk8 levels.
Preventive treatment For Heart Failure
When the researchers examined the heart cells of the mice before a decrease in heart function was detectable, they found that more than 3,400 genes already were expressed with a profile similar to that of human heart muscle cells with dilated cardiomyopathy and heart failure.
"Other studies have looked at tweaking the contraction and metabolism in heart cells as a possible cure for heart failure," Hall says. "Our study is one of the first to show that something in the cell nucleus is capable by itself of inducing the structural changes that occur in heart failure."
The study results suggest that modifying gene expression may provide a path to preventive treatments for heart failure.
"In terms of disease progression, heart failure is the end stage. Our study suggests that the transition, or 'switch,' from a stressed, enlarged heart to a failing heart is key," Grueter says. "Looking ahead, hopefully we'll be able to test whether a drug can block that switch from occurring."
- Duane D. Hall et al., Ectopic expression of Cdk8 induces eccentric hypertrophy and heart failure, JCI Insight (2017) http:dx.doi.org/10.1172/jci.insight.92476.