Activated protein C suppresses cardiomyocyte senescence in diabetic cardiomyopathy via PAR1/PAR3-P85-CaMKIIδ axis
Year: 2025
Type: other
Abstract: 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 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 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 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 via PAR1/PAR3-P85-CaMKIIδ axis.
Authors: Yueqi Zhang, Lei Dai, Mengwen Wang, Xiaodan Zhong, Xiaolei Liu, Kaiyue Zhang, Lingyun Luo, Lingyun Wang, Wei Dong, Alexandra Vaczy, Lina Li, Tamas Atlasz, Thati Madhusudhan, Chang Xu, Hongjie Wang, Hesong Zeng
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4413381041