Abstract
ABSTRACT
Background
Diabetes mellitus is commonly featured with cardiac microvascular dysfunction and chronic low‐grade inflammation, contributing to the progression of diabetic cardiomyopathy (DCM). Finerenone confers cardio‐renal protection in diabetic settings, yet its underlying mechanisms remain incompletely defined.
Aim
To explore the beneficial effects and molecular mechanisms of finerenone on cardiovascular dysfunction in uncontrolled DCM from the perspectives of neutrophil extracellular traps (NETs) formation and AKT1 phosphorylation.
Methods
Finerenone was orally administrated to db/db mice for 24 weeks. Global AKT1 S473A mutation mice and bone marrow chimera mice were subjected to high‐fat diet and streptozotocin‐induced diabetic mouse model. Proteomics, pharmacological network analysis, and cellular thermal shift assay were employed to identify potential molecular targets of finerenone. Multiple approaches, including immunoblotting and immunofluorescence, were used to detect NETs and related cardiac injury.
Results
Finerenone treatment significantly improved cardiac and microvascular injury in uncontrolled DCM, as indicated by increased microvascular density, reduced vascular leakage, and alleviated cardiac remodeling. In addition to the mineralocorticoid receptor, AKT1 phosphorylation at S473 was identified as a direct target of finerenone. Finerenone improved AKT1 phosphorylation in endothelial cells to maintain vascular barrier function and reduce damage‐associated molecular patterns (DAMPs) release, thereby suppressing polymorphonuclear (PMN) infiltration and NETosis. In contrast, AKT1 phosphorylation in PMN was suppressed by finerenone for NETs inhibition and related cardiac injuries. Similarly, global and cardiac AKT1 S473A mutation accentuated uncontrolled DCM, whereas myeloid AKT1 S473A mutation improved uncontrolled DCM.
Conclusion
Finerenone treatment mitigated microvascular dysfunction, DAMPs release, and NETs‐associated cardiac injury via balancing AKT1 phosphorylation across different cell types, contributing to its cardiovascular protection in uncontrolled DCM.