From heart attack to heart failure:
According to the U.S. Centers for Disease Control and Prevention, 6.7 million Americans over the age of 20 have heart failure, which occurs when the heart is unable to pump enough blood to the rest of the body. After developing heart failure, 52.6% of patients die within five years. The most significant cause of heart failure is a heart attack, which affects more than 800,000 Americans each year.
When a person suffers a heart attack, their heart muscle often becomes damaged due to a lack of oxygen and increased oxidative stress. This damage can lead to inflammation and scarring, which eventually weakens the heart and causes heart failure. Although current treatments exist to restore blood flow, these methods do not fully prevent the long-term damage that leads to heart failure over time.
To address this unmet need, the research team focused on the interaction between two proteins: Keap1 and Nrf2. While Nrf2 protects heart cells from stress and inflammation, Keap1 physically binds to Nrf2, regulating its function. This prevents Nrf2 from entering the cell’s nucleus, where it can activate protective genes.
“Based on past biological studies, Nrf2 has been shown to have a positive effect on heart health following heart attack,” Gianneschi said. “We wanted to see if boosting Nrf2 could act to help the body heal itself after a heart attack.”
Freeing protective proteins:
In previous studies, Gianneschi and his colleagues invented the PLP platform, in which nanoscale precision polymers mimic proteins to act like artificial antibodies. Once inside cells, they “grab” biological targets. In the new study, Gianneschi, Christman and their teams engineered a PLP with multiple “arms” that can grab onto Keap1. These “arms” mimic a part of the Nrf2 protein that typically binds to Keap1.
Because it has many “arms,” the PLP binds strongly to Keap1, preventing it from grabbing onto the real Nrf2. With Keap1 out of the way, Nrf2 can move into the heart cell’s nucleus to exert its protective effects.
After developing the system, the researchers conducted laboratory tests on heart muscle cells to evaluate its effectiveness. In experiments, the PLPs — even at very low concentrations — successfully protected cells from damage caused by oxidative stress. Next, the team administered a single dose of PLP intravenously in a small animal model of heart attack. Not only did the therapy improve how well the animal’s heart functioned, it also remained effective up to five weeks after the injection. Further testing showed the cells expressed more Nrf2-related genes, which promote healing.
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