Elevated amino acid levels diminish the DNA Damage Response and increase the risk of heart failure 🫀
Heart failure is the leading cause of death in the world. A variety of risk factors contribute to heart failure. How exactly each of these factors contributes to heart failure is still being actively researched.
A new study, now published in the journal Cell Reports, has shed light on one of the metabolic pathways leading to heart failure.
The authors of the study started by comparing the amount of metabolites in the blood plasma of healthy people and patients with heart failure. They noticed a >20% increase in the levels of the amino acid tyrosine in patients.
To validate their finding, they fed experimental mice with a high-tyrosine diet. In a few weeks, these mice showed symptoms of heart failure. They also measured a significant increase in DNA damage in mice hearts fed with a high-tyrosine diet.
They also tested the effects of high tyrosine in cultured human cells. They observed an increase in DNA Damage with an increase in tyrosine concentration supplied to cells. Surprisingly, with this concomitant increase in DNA Damage, they observed a decrease in the cellular response to DNA Damage. This means that cells were not responding or fighting back the DNA damage.
They elaborated on the mechanism by which increased tyrosine levels block the DNA Damage Response in cells. They showed that excess tyrosine blocks the enzyme that attaches tyrosine to the key DNA Damage kinase ATR. Tyrosylated-ATR is important to activate the DNA Damage Response. Artificially attaching tyrosine to ATR restored the DNA Damage Response, confirming their findings.
The authors conclude by writing that their findings support the relationship between dysregulated amino acids and human diseases. The authors also write,
Our findings also give mechanistic meaning to observations where high protein intake was associated with an increased risk of heart failure…
In particular, increased consumption of red meat and processed red meat, both rich in tyrosine, may be associated with increased risk of heart failure.
Thus, protein restriction, especially a phenylalanine/tyrosine-restricted diet, could benefit heart function.