High-Throughput Screening of an FDA-Approved Compound Library Reveals a Novel GAS6 Receptor Agonist for Therapeutic Intervention in Septic Myocardial and microvascular Injury via Modulation of Danger-Associated Molecular Patterns.

Abstract

PGAM5 and VDAC1 have both been reported to regulate mitophagy. However, the mechanisms by which they regulate sepsis-induced inflammatory microvascular injury remain unverified. In previous studies, we established the role of this regulatory axis in various phenotypic processes, including mitophagy, mitochondrial biogenesis, the mitochondrial unfolded protein response, and mitochondrial dynamics, while further confirming the interactive regulatory proteins within this axis. However, the validation and elucidation of these regulatory phenotypes have primarily focused on ischemic heart diseases such as ischemic myocardial injury and heart failure. Sepsis-related myocardial injury is currently recognized as a significant cardiac impairment, and although there are cardioprotective and nutritional agents available for supportive therapy, fundamental research validating the upstream targets and mechanisms of microvascular injury is still lacking. Based on our previous research, we further explored the role of mitophagy dysfunction mediated by VDAC1 and its upstream regulatory protein PGAM5 in sepsis-induced coronary microvascular injury. We also confirmed the material basis and metabolic pathway regulation targeting the PGAM5- VDAC1 interactive mechanism with relevant drugs. Our findings suggest that PGAM5-mediated mitophagy dysfunction may be a crucial factor leading to sepsis-induced microvascular injury, primarily interacting with VDAC1-mediated mitochondrial membrane dysfunction. Animal experiments revealed that cardiac-specific knockout of PGAM5 could reverse LPS-induced coronary microvascular injury and inflammatory damage, restoring cardiac ejection function and mitophagy functionality. In vitro studies also confirmed that the PGAM5-VDAC1 interaction can normalize mitophagy, restoring the normal morphology and structure of mitochondria while maintaining normal mitochondrial energy metabolism levels and respiratory chain function. Further pharmacological research indicated that the active ingredients of traditional Chinese medicine-Puerarin (TCM, a GAS6 Receptor Agonist) can target the PGAM5- VDAC1 axis to regulate mitophagy and inhibit LPS-induced necrotic apoptosis in cardiomyocytes, potentially reversing mitochondrial pathway-related cardiac injury. TCM may emerge as a prospective therapeutic agent targeting the PGAM5- VDAC1 axis.