Activated Protein C Suppresses Cardiomyocyte Senescence in Diabetic Cardiomyopathy via PAR1/PAR3-P85-CaMKIIδ Axis

Diabetic cardiomyopathy (DbCM) is a chronic metabolic disorder with few effective treatment strategies. Our previous study demonstrated that activated protein C (aPC), a serine protease, exerts cytoprotective effects in DbCM. However, the mechanisms underlying its role in DbCM require further elucidation. We developed a type 1 diabetic mouse model using thrombomodulin gene point mutation mice (TMP/P) with reduced endogenous aPC generation and investigated the protective effects of aPC on DbCM through intraperitoneal injection of PC. Myocardial functions and structure were assessed by echocardiography and histology. Transcriptomic analysis and immunological evaluation were conducted to investigate the downstream targets. The antisenescence role of aPC was reaffirmed by PC treatment in vivo and aPC intervention in cultured neonatal rat ventricular myocytes in vitro. Endogenous aPC levels were reduced and positively correlated with cardiac diastolic function in diabetic mice. Cardiomyocytes manifested a senescent phenotype in DbCM. With impaired aPC activation, TMP/P mice exhibited aggravated diabetes-induced cardiac dysfunction and cardiomyocyte senescence. Mechanistically, aPC alleviated cardiomyocyte senescence in DbCM by acting on PAR1/PAR3 to restore the interaction between P85 and CaMKIIδ, thereby inhibiting CaMKIIδ phosphorylation and its nuclear translocation. In summary, our study highlights that aPC ameliorates cardiomyocyte senescence in DbCM via the PAR1/PAR3-P85-CaMKIIδ axis. ARTICLE HIGHLIGHTS: Diabetes exacerbates cardiomyocyte senescence, leading to an accelerated decline in cardiac function. The systemic levels of activated protein C (aPC) were reduced, which correlated with deterioration of cardiac diastolic function in diabetic cardiomyopathy (DbCM), while the underlying mechanisms remained unclear. We aim to identify the role of aPC in ameliorating cardiomyocyte senescence in DbCM. We highlighted that aPC ameliorated cardiomyocyte senescence in DbCM via the PAR1/PAR3-P85-CaMKIIδ axis with genetic (TMP/P) and interventional (PC injection) diabetic mouse models. These findings could lead to increased insight into the pathogenesis and innovative therapeutic approaches of diabetic cardiomyopathy.