For a while now, heart disease researchers have known that a protein called GRK5 – expressed throughout the body, though most notably in the lungs, heart, and placenta – normally dwells in the outer membrane of heart cells and, upon exposure to stress, moves into the cell nucleus, switching on a host of genes that lead to cardiomyopathy (thickening of the heart tissue).
Now, in a study published on 30 March in Science Signaling, researchers from the Center of Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, have demonstrated the possibility of improving heart health by blocking GRK5 from entering the cell nucleus.
For this purpose, the researchers developed a truncated version of GRK5, a peptide dubbed GRK5nt, which binds to calmodulin – a protein that enables GRK5 to reach the nucleus – but doesn’t turn on the genes that lead to heart failure.
The risk of heart failure could be reduced by preventing a key protein from entering the cell nucleus and triggering the expression of harmful genes. Image: Macro Mama via stocksnap.io, CCO Public Domain
Lead author on the study Wally Koch called GRK5nt a “calmodulin sponge” – by way of binding to calmodulin, the peptide (GRK5nt) effectively neutralises the protein “stores”, leaving only a small amount for regular GRK5 to bind to.
To test their hypothesis, the researchers genetically engineered a group of mice to express GRK5nt in addition to regular GRK5, and surgically altered some of the mice to put additional pressure on the heart. The other mice received a sham (placebo) surgery to rule out any confounding factors.
Results showed that after eight weeks, the control group (the mice that received surgery) had thicker, less efficient hearts than mice that underwent the sham surgery. On the other hand, the genetically engineered mice showed much less damage to their heart tissue.
In addition, the control group had large amounts of GRK5 in the nuclei of their heart cells, whereas the experimental group did not. “So our hypothesis was true,” said Koch. “If you actively keep GRK5 out of the nucleus, it leads to beneficial effects”.
The “decoy” GRK5nt was also found to cause no adverse cardiac effects in mice that received sham surgery. Similarly, none of the cellular processes that rely on calmodulin were affected, although, by the authors’ own admission, the search was not extensive and therefore necessitates further study.
Before the peptide is approved as a therapeutic substance for treating humans, Koch and his team plans to test it on regular mice with heart failure, but without the presence of GRK5nt in their systems since birth. If successful, this may eventually lead to clinical trials in human subjects.