Recent research has identified Serpina3k lactylation as a protective mechanism against cardiac ischemia-reperfusion injury (IRI), which occurs when blood supply returns to the heart after ischemia or lack of oxygen.
The balance between myocardial blood flow restoration and cellular damage is delicately poised, as the very act of restoring blood flow can lead to severe complications, exacerbated cellular dysfunction, and increased risk of heart failure. Researchers at Fuwai Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical University have provided new insights, highlighting the protective role of the protein Serpina3k during this process.
Despite advancements like thrombolytic therapy and percutaneous coronary intervention improving outcomes for myocardial infarction (MI) patients, IRI remains a significant risk factor contributing to cardiovascular damage. This study focuses on the effects of lactate, which accumulates during ischemia, and its impact on protein function through the novel process of lactylation. The authors found evidence of significant lactylation of proteins, particularly identifying up to 1,674 lactylation sites across 380 proteins post-IRI.
Among these, Serpina3k, which is primarily expressed by cardiac fibroblasts rather than cardiomyocytes, emerged as a central player due to its lactylation at lysine 351 (K351). This modification was shown to stabilize the protein, enhancing its protective capacity against apoptosis—a type of programmed cell death—triggered by IRI.
"Ischemia-reperfusion injury can exacerbate cellular dysfunction and death, impacting cardiac function and structure," noted the authors of the article. The lactylation of Serpina3k not only improves its stability but also prompts cardiac fibroblasts to secrete this protective protein, which then acts on nearby cardiomyocytes. This paracrine signaling process helps shield these heart cells from damage during reperfusion, activating pro-survival kinase pathways known as reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE).
The significance of this discovery lies both in its potential clinical applications and its contribution to the broader scientific dialogue surrounding heart repair mechanisms after ischemic events. Current therapies targeting IRI have shown limited efficacy due to the incomplete characterization of molecular changes during reperfusion. By mapping out how lactate influences protein modifications, especially lactylation, this study opens new avenues for therapeutic strategies.
The researchers conducted mass spectrometry-based proteomic and lactylome profiling to conclusively establish their findings. Their comprehensive analysis revealed Serpina3k's high stability and lactylation levels significantly increased at the K351 site within just one hour of reperfusion. "Our results demonstrate the pivotal role of protein lactylation in cardiac ischemia-reperfusion injury, which may hold therapeutic value," the authors concluded.
These findings suggest the potential of leveraging Serpina3k and its lactylation status as therapeutic agents to mitigate cardiac injury. Future research may focus on refining and deploying such protein-based strategies to improve patient outcomes following myocardial ischemia.
Successful interventions could hinge upon enhancing or mimicking the protective effects of lactylation, alongside control of lactate levels themselves. Therefore, this research not only sheds light on the mechanisms at play during cardiac injury but also sets the stage for the development of more effective, targeted treatments for heart conditions stemming from ischemia.
By continuing to study and capitalize on the role of cardiac fibroblasts and the proteins they secrete, clinicians may soon have access to novel therapies aimed at protecting heart tissue from ischemic damage, potentially improving recovery outcomes for millions of patients suffering from ischemic heart diseases.