Increasing ALDOC improved heart function and reduced scarring in adult mice after a heart attack
Increasing ALDOC improved heart function and reduced scarring in adult mice after a heart attack
A study published on September 8 in Cell Death & Disease describes an experiment in adult male mice given the Aldoc gene by injection into the heart muscle immediately after a heart attack. After 28 days, their hearts pumped blood more effectively and had smaller scars than those of control animals.
After a heart attack, dead cardiomyocytes, the muscle cells whose contractions pump blood, are largely replaced by scar tissue in the adult heart. Newborn mice retain the ability to replace these cells after injury for a short time. The authors took this difference as their starting point and selected ALDOC, an enzyme involved in glucose breakdown. Its level in the mouse heart is high on the first day of life, falls sharply by the seventh day, and rises again after heart injury in newborn mice.
In cell experiments, increasing ALDOC enhanced glucose breakdown and markers of cardiomyocyte division; suppressing ALDOC reduced both. In newborn mice whose heart apex had been removed, ALDOC suppression was associated with poorer pumping function and larger scars after 28 days.
The authors conducted their main test in adult male mice. They tied off the left anterior descending coronary artery to induce a heart attack, then immediately injected AAV9, a viral vector carrying the Aldoc gene, at three sites near the injured area. Control animals received the same vector without Aldoc; each group contained six mice. On day 28, the ejection fraction, a measure of the heart's pumping function, was 56,74% in the Aldoc group and 36,50% in the control group. Scar tissue occupied 21,80% of the left ventricular area, compared with 41,95% in controls.
The authors traced the steps linking the intervention to this outcome. ALDOC interacted with RBM39, a protein involved in RNA processing. When ALDOC levels were increased, RBM39 was less frequently tagged with ubiquitin, which marks proteins for degradation, allowing RBM39 to persist longer. Activity in the PI3K/AKT signaling pathway, which is involved in initiating cell division, also increased. In cell experiments, an inhibitor of this pathway reduced markers of cardiomyocyte division. In the heart attack model, suppressing Rbm39 reduced the benefits of ALDOC for heart pumping function and scar area.
The authors thus connected their observation in newborn mouse hearts to an experiment in adult mice after a heart attack: they increased ALDOC, measured scar area and pumping function, and then showed that the outcome depended on RBM39.