GDF15 attenuates myocardial infarction-induced injury by preserving mitochondrial function and suppressing oxidative stress.

Abstract

Myocardial infarction, a serious cardiovascular disease, is still a major cause of morbidity and mortality worldwide. Growth differentiation factor-15, a stress-responsive cytokine, has been involved in cardiac pathophysiology, but its exact role in myocardial infarction remains controversial. This study aimed to clarify the mechanisms underlying the cardioprotective effects of GDF-15 in myocardial infarction. By using a combination of in vivo and in vitro methods, including immunofluorescence staining, echocardiography, RNA sequencing, and high-resolution respirometry, we showed that GDF-15 expression is significantly upregulated in infarcted myocardium and its deficiency aggravates cardiac injury. Mechanistically, GDF-15 deficiency impairs mitochondrial function and energy metabolism under hypoxic stress, as evidenced by changes in mitochondrial membrane potential and respiratory parameters. Moreover, we identified that GDF-15 suppresses hypoxia-induced reactive oxygen species generation through activation of the AMPK signaling pathway. Therapeutic administration of exogenous GDF-15 reduces myocardial injury, hypoxic stress, and fibrosis after myocardial infarction, suggesting its potential as a therapeutic target. These findings collectively demonstrate that GDF-15 plays a crucial role in cardiac protection during myocardial infarction by regulating mitochondrial function, energy metabolism, and oxidative stress. Our results provide novel insights into the molecular mechanisms of GDF-15-mediated cardioprotection and suggest its potential as a therapeutic intervention for myocardial infarction. Future studies should focus on translational research to evaluate the clinical efficacy of GDF-15-based therapies in myocardial infarction patients.