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Beta-Blocker Treatment Could Undo Gene Expression Changes in Heart Failure

NEW YORK (GenomeWeb) – Beta-blocker treatment may undo some of the gene expression changes that occur in heart failure, according to a new study.

Beta-blockers are commonly used to treat cardiac conditions, including heart failure, and they target myocyte enhancer factor 2 (MEF2) proteins, which are involved in cardiac remodeling.

Through RNA sequencing, researchers from York University in Toronto uncovered some 65 genes that are differentially expressed in a mouse model of heart failure versus control mice. But as they also reported today in Scientific Reports, some of those expression changes could be undone with beta-blocker treatment.

"We discovered that beta-blockers largely reverse the pathological pattern of gene expression observed in heart failure," senior author John McDermott, a professor at York, said in statement. "This could mean that the reversal or suppression of pathological gene expression by beta-blockers is somehow protective against heart failure, but it's something we would need to look into further to understand how individual genes function in the heart."

McDermott and his colleagues used a surgical technique to simulate heart failure in a cohort of mice. The mice that underwent that procedure exhibited the physical characteristics of cardiac hypertrophy and the early stages of heart failure as well as increased MEF2 activity, while the mice that underwent a sham procedure did not.

Mice from each of those groups then received either treatment with the beta-blocker atenolol or a solvent.

After four weeks of treatment, the researchers found that the mice with heart failure that were given the placebo still exhibited signs of cardiac dysfunction, while the mice with heart failure that were given atenolol had improved and had decreased MEF2 activity. Meanwhile, the mice without heart failure that were given atenolol had no difference in heart function when compared to the mice that underwent sham surgery and were given placebo.

McDermott and his colleagues also collected samples from the left ventricles of three mice from each group for RNA sequencing. From this, they uncovered 65 genes that were differentially expressed between the mice with induced heart failure and the mice without heart failure that both received placebo.

But they also noted that about half those genes also differed between the mice with induced heart failure that were given the drug and the mice with induced heart failure that were not given the drug. These differentially expressed genes included Klf2, Junb, Alas2, and Rarres2, among others.

Generally, genes that were upregulated in the untreated mice with heart failure were downregulated in mice with heart failure given the drug, and vice versa.

This, and their RT-qPCR-based replication work, indicated to the researchers that atenolol treatment might be able to reverse the effect that induced heart failure has on gene expression.

In a series of assays in cardiomyocytes in which MEF2 was silenced, the researchers likewise found a number of differentially expressed genes. In particular, they noted that Rarres2 appeared to be a novel MEF2 target gene.

A gene ontology analysis of these differentially expressed genes suggested that they are involved in processes related to cell death, cell migration, and the inflammatory response.

"These studies identify a cohort of genes with vast potential for disease diagnosis and therapeutic intervention in heart failure," the researchers wrote in their paper.