Research from the University of Wisconsin – Madison has shown that a new therapeutic approach to heart failure can help restore heart function by regenerating the heart muscle.
In a study recently published in the journal Circulation, the UW team describes their success in improving myocardial function in a mouse model by temporarily blocking a key metabolic enzyme after a heart attack. This simple intervention, say the researchers, could ultimately help people regain their heart function.
“Our aim was to gain a new understanding of how the heart can heal itself at the molecular and cellular level after an injury, and to find out whether there is a way to restore the heart to an earlier state,” says Ahmed Mahmoud , Professor of Cells at UW-Madison and Regenerative Biology at the School of Medicine and Public Health. “We know that after birth, a metabolism occurs in the heart that contributes to the loss of the ability to regenerate the heart. However, we did not know which mechanisms regulate this metabolic switch. This is where we started our research. “
This metabolism involves changing the way cells produce energy, moving from a process called glycolysis to a process called oxidative phosphorylation.
Previous studies have shown that a metabolic compound made by cells called succinate can build up in the heart when it is deprived of oxygen, such as during a heart attack. This can trigger a cascade of events that lead to the production of harmful molecules called reactive oxygen species that can damage heart cells.
Previous studies also showed that blocking another cellular connection, succinate dehydrogenase, can prevent succinate accumulation and subsequent damage. The inhibition of the compound can also lead to a metabolic shift of the cells to glycolysis, which promotes cardiac regeneration.
Mahmoud’s team investigated whether they could change this metabolic switch and preserve the heart’s ability to regenerate after damage. Initially, they focused on succinate, which reduced the regeneration of new heart cells in newborn mice and caused DNA damage after a myocardial infarction.
In young mice, the research team used a metabolite called malonate, which blocks succinate dehydrogenase, to determine whether the heart cells’ ability to regenerate after a heart attack is retained. The treatment not only resulted in complete heart regeneration, but also restored heart function.
To make sure the effects were due to inhibiting succinate dehydrogenase, the research team used another inhibitor, a compound called atpenin A5, and found effects similar to malonate.
“We believe our results represent a positive step forward to helping millions of people with heart failure.”
In adult mice, the researchers also tested whether, as in young mice, malonate can restore the heart’s ability to regenerate after a myocardial infarction. They found that it boosted the production of new heart cells, helped deliver new blood vessels to the area damaged by the infarct, and led to heart regeneration. It also confirmed the finding that inhibiting succinate dehydrogenase helps the heart switch from oxidative phosphorylation to glycolysis.
“Both vascular and myocardial damage result from acute cardiovascular events such as myocardial infarction,” explains Mahmoud. “The adult heart’s limited ability to repair itself is a major barrier in cardiovascular medicine and often leads to heart failure. Our research shows that it may be possible to improve the function of the heart muscle after a heart attack, which is good news for people with systolic heart failure. “
Heart failure remains a significant problem in the United States. Heart failure affected 6 million American adults between 2015 and 2018, according to the American Heart Association. It is a chronic, progressive disease that decreases the heart’s ability to pump blood well. Heart failure can be caused by myocardial infarction, and every 39 seconds an American has a heart attack.
The researchers say malonate and the inhibition of succinate dehydrogenase in general require further study. For example, malonate in the adult heart increased succinate levels in the mice two weeks after the heart attack, suggesting that it actually promotes metabolic reprogramming of the heart into a regenerative state rather than preventing the metabolite from accumulating.
Succinate dehydrogenase is also a tumor suppressor, so it is important to better understand the effects of inhibition in relation to a heart attack. In addition, the researchers believe that finding ways to treat malonate specifically for the heart is important.
“Understanding the effects of malonate on the heart and other tissues will be an essential step before our results on the treatment of heart failure are rolled out in the clinic,” says Mahmoud. “We believe our results represent a positive step forward to helping millions of people with heart failure.”
The team is currently investigating whether malonate could regenerate the hearts of larger animals and are working to better understand the long-term effects of brief inhibition of succinate dehydrogenase.
Funding for this project was provided by the UW School of Medicine and Public Health through the Wisconsin Partnership Program, a career development award from the American Heart Association 19CDA34660169, NIH / NCATS, through the CTSA award UL1TR002373 to the UW Institute for Clinical and Translational Research, a postdoctoral training provided award from the Stem Cell and Regenerative Medicine Center at UW-Madison and NIH / NHLBI under Ruth L. Kirschstein NRSA T32 HL007936 to the UW Cardiovascular Research Center.