<b>Activated protein C </b><b>suppresses cardiomyocyte senescence</b><b> in diabetic cardiomyopathy via </b><b>PAR1/PAR3-P85-CaMKIIδ axis</b>

<p dir="ltr"><a href="" target="_blank">Diabetic cardiomyopathy</a> (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.<a href="" target="_blank"> We developed a type 1 diabetic mouse model using thrombomodulin gene point mutation mice (TM<sup>P/P</sup>) with reduced endogenous aPC generation and investigated the protective effects of aPC on DbCM through intraperitoneal injection of protein C (PC). Myocardial functions and structure were assessed by echocardiography and histology. Transcriptomic analysis and immunological evaluation were conducted to investigate the downstream targets. The anti-senescence role of aPC was reaffirmed by PC treatment <i>in vivo</i> and aPC intervention in cultured neonatal rat ventricular myocytes <i>in vitro</i>. Endogenous aPC levels were reduced and positively correlated with cardiac diastolic function in diabetic mice. Cardiomyocytes manifested a senescent phenotype in DbCM. With </a>impaired aPC activation, TM<sup>P/P</sup> mice exhibited aggravated diabetes-induced cardiac dysfunction and cardiomyocyte senescence. Mechanistically, aPC alleviated cardiomyocyte senescence in DbCM by acting on PAR1/PAR3 receptors 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 <i>via</i> PAR1/PAR3-P85-CaMKIIδ axis.</p>