Complement C3a plays a role in diabetic cardiomyopathy mainly via C3aR-ERK-PANoptosis pathway

Diabetic cardiomyopathy (DCM) is one of the leading causes of death in diabetic patients. However, the pathogenesis of DCM remains incompletely understood, and effective targeted therapies are lacking. This study aims to investigate the role of complement C3a in the development of DCM, providing a novel theoretical foundation for its precise prevention and treatment.

Eight-week-old male C57BL/6 J mice were injected with streptozotocin (STZ) to induce a diabetes model for 26 weeks. The two intervention groups were injected with C3a receptor antagonist (SB290157, 30 mg/kg/d) and novel C3 cleavage inhibitor (CP40-KK, 2 mg/kg/d) by intraperitoneal injection for 8 weeks. Cardiac function/histopathological changes were determined by echocardiogram examination, and Millar catheter system. Human cardiomyocytes (AC16) were employed in vitro.

C3a was significantly upregulated in the plasma of the STZ-induced DCM model, and PANoptosis plays a critical role in cardiac tissue and cardiomyocytes. The C3a receptor antagonist (SB290157) could significantly improve the cardiac function of diabetic mice, reduce myocardial hypertrophy, and inhibit the activation level of PANoptosis pathway in cardiac tissue. Furthermore, inhibiting the C3aR/ERK pathway could regulate cardiomyocyte PANoptosis by pyroptosis (NLRP3-dependent), apoptosis (caspase-3-dependent), and necroptosis (RIP-dependent) in the DCM model and C3a-treated cardiomyocytes. The novel complement C3 inhibitor CP40-KK exerts comparable therapeutic efficacy to SB290157 in treating DCM at a lower drug dosage.

We demonstrate the crucial role of the C3a/C3aR signaling axis, and CP40-KK treatment was protective in the STZ-induced DCM model. These findings provide valuable evidence supporting potential complement-based therapies targeting the C3a/C3aR/ERK/PANoptosis pathway in DCM treatment.