Traditional beta-blockers target beta1-adrenergic receptors, which helps to prevent heart cells from dying and exacerbating a case of heart failure. However, beta1-adrenergic are also responsible for helping the heart to continue pumping blood to carry oxygen to the body tissues. For the almost six million Americans who suffer from heart failure, scientists were desperately seeking out a way to improve beta-blockers to both save dying heart cells and preserve the pumping abilities of the heart muscle. For scientists from Thomas Jefferson University, this discovery and much more followed after careful experimentation.
The Thomas Jefferson University researchers found their solution by altering the target pathway of beta-blockers. Rather than targeting beta1-adrenergic receptors, they designed a molecule called a "pepducin," which was created from partsof the beta2-adrenergic receptor. Pepducins, they found, naturally activates beta2-adrenergic receptors and only these receptors, potentially bypassing the negative effect beta-blockers have on the pumping action of the heart without giving up on saving dying heart cells.
The alternate pathway of treating heart failure, said senior author of the study Jeffrey Benovic, PhD, is "an excellent example of how a little curiosity in the basic research laboratory can lead to discoveries that have the potential to change the way we treat a very common and very deadly illness." The Centers for Disease Control and Prevention estimate that half of all people with heart failure will die from the disease within five years.
The discoveries didn't stop with pepducins and beta2-adrenergic receptors. While studying the structure of pepducins in finer detail, one of the team scientists noticed that the pepducins they had designed looked a lot like an existing treatment for heart failure, a drug called carvedilol. This drug targets both beta-1 and beta-2 adrenergic receptors as well as alpha-receptors to lower blood pressure, relax arteries, and even acts as an antioxidant, eliminating free radicals in the blood. Realizing the similarities between pepducins and carvedilol pushed the scientists to dive even further into the true power of pepducins. What they found was astronishing.
They discovered that pepducins not only preserved the beating abilities of cardiomyocytes, but they enhanced the force of the beating to a higher level. This discovery was especially shocking because until now, researchers were not aware that beta2-adrenergic receptors were capable of impacting the beating function of the heart. Since pepducins uniquely activate beta2-adrenergic receptors, they knew it was this pathway that was stimulating the forceful heart beat.
Next the identified a secondary signaling molecule called beta-arrestin as the intermediary force behind the heart cells beating, with activation of pepducins leading to contraction of cardiomyocytes increased by up to 50 percent. However, with the right tweaking, researchers from the study believe they could get pepducins enhancing cardiomyocyte contraction up to a full 100 percent.
"If we find or design a compound that works like this pepducin, it wouldn't necessarily cure heart disease, but it would give doctors another tool to help bolster a failing heart," Benovic said. He and his team are now working on improving pepducin before bringing it into clinical trials. It may be a little while longer, but it seems as if the future of heart failure treatment is on the way.
This study was recently published in the Proceedings of the National Academy of Sciences.
Sources: Thomas Jefferson University