Elevated isatin ameliorates heart injury in patients with myocardial infarction after rehabilitation treatment-based metabolomics screening

BACKGROUND: Rehabilitation exercise after acute myocardial infarction is helpful for cardiac function recovery. Isatin, an endogenous indole derivative of tryptophan metabolism, exhibits anti-inflammatory and antioxidant properties, but its role in myocardial injury repair post-myocardial infarction (MI) remains unclear. PURPOSE: This study aimed to investigate isatin's cardioprotective effects and molecular mechanisms in post-rehabilitation AMI patients through multi-omics approaches. STUDY DESIGN: This study aimed to systematically investigate the protective effects and molecular mechanisms of isatin on cardiac injury in patients with AMI following rehabilitation, using untargeted metabolomics, HuProt™ microarray, network pharmacology (NP), surface plasmon resonance (SPR), molecular docking, molecular dynamics (MD), animal models, and cell experiments. METHODS: -treated cardiomyocytes and LPS-treated macrophages were used to explore the potential protective mechanisms of isatin. RESULTS: EECP elevated serum isatin in STEMI patients, correlating with better cardiopulmonary function. S100A8 was identified as the primary target by HuProt™ microarray and NP. Isatin formed a 2.1 Å hydrogen bond with S100A8-GLU41. SPR KD=57.9 μM; Docking score=-5.37 kcal/mol; MD ΔG=-15.35 ± 1.95 kcal/mol. Isatin improved cardiac function in AMI mice. Isatin enhanced HL-1 cardiomyocyte viability while reducing apoptosis, and decreased macrophage IL-1β, IL-6, IL-1α, and TNF-α secretion. CONCLUSION: This study demonstrates that EECP enhances cardiac rehabilitation in STEMI patients by upregulating endogenous isatin, which exerts cardioprotective effects through direct targeting of S100A8, leading to improved cardiac function and reduced oxidative stress and inflammation, with the molecular mechanism confirmed by integrated multi-omics analyses.