Heart Attack Recovery Breakthrough: Protein Modification Controls Immune Response

Heart attacks remain a leading cause of death worldwide, with much of the damage occurring not during the initial blockage, but during reperfusion when blood flow is restored. This study reveals a previously unknown mechanism driving this harmful inflammation through a protein modification called lactylation.

Researchers used advanced proteomics to analyze neutrophils (key inflammatory immune cells) in mice after heart attacks. They discovered that S100a9, an inflammatory protein, becomes lactylated at a specific site (lysine 26) during the metabolic stress of heart injury. This modification dramatically alters the protein's behavior, causing it to move into cell nuclei where it acts as a genetic switch, turning on genes that promote neutrophil migration to the heart.

Using genetically modified mice that couldn't undergo this S100a9 lactylation, the team demonstrated remarkable protection from heart attack damage. These mice showed 60% better heart function, dramatically reduced inflammation, and less cardiac fibrosis compared to normal mice. The protective effect was specifically due to neutrophil behavior, as transferring normal neutrophils into protected mice restored the damage.

The researchers identified DLAT, an enzyme involved in cellular metabolism, as responsible for adding the lactyl modification to S100a9. Importantly, they found that α-lipoic acid, an existing supplement, could block this process. In human patients, elevated levels of lactylated S100a9 in blood correlated with heart damage markers and predicted worse outcomes.

This discovery opens new therapeutic avenues for heart attack treatment, potentially through targeting the DLAT enzyme or using α-lipoic acid supplementation. The lactylated S100a9 protein also shows promise as a biomarker for identifying patients at highest risk for poor recovery after heart attacks.