Activated protein C (APC) was first identified as a natural anticoagulant enzyme. Besides its anticoagulant activity, APC exerts cytoprotective effects such as anti-inflammatory and anti-apoptosis. It has revealed that APC reduces the mortality rate and apoptotic rate during cardiac ischemia and reperfusion. However, the mechanism involved in cardioprotection stimulated by APC is still unclear. The objective of this project is to illustrate the mechanism by which APC mediates cardioprotection against ischemic injury. Our preliminary data demonstrated that the administration of APC reduced myocardial infarction during ischemia and reperfusion. AMP-activated protein kinase (AMPK), a cardioprotective signaling, was activated in APC treated mouse heart. Moreover, ischemia and reperfusion-induced stress-activated protein kinase (SAPK/JNK) signaling was attenuated by APC treatment. We hypothesize that APC protects against myocardial ischemic injury by triggering crucial signaling pathways to modulate substrates metabolism and reducing inflammatory response under ischemic stress.
Three specific aims will be addressed to test the hypothesis: 1) determine the modulation of AMP activated protein kinase signaling by APC derivatives during ischemia and reperfusion in the heart; 2) determine the effect of APC derivatives on inflammatory response during ischemia and reperfusion in the heart; 3) determine the mechanisms by which APC modulates glucose transport that reduces ROS responsible inflammatory response in the ischemic heart. APC may decrease the pro-inflammatory factors during cardiac ischemia and reperfusion to reduce heart injury. We also will figure out whether anticoagulant domain of APC is not important for its cardioprotction against ischemia and reperfusion injury, which will provide evidence that recombinant APC without anticoagulant activity can be used for therapy of ischemic heart disease without risk of bleeding.
The project aims to characterize the cardioprotection of an endogenously produced anti-coagulant protein, activated protein C (APC), against ischemic injury. The study also explores the signaling mechanisms underlying APC?s role in regulating substrate metabolism thereby modulating heart?s response to ischemic insults. The results from these findings could lead to novel therapeutic strategies aimed at limiting cardiac damage for myocardial infarct patients.
|Li, Xuan; Liu, Jia; Hu, Haiyan et al. (2018) Dichloroacetate ameliorates cardiac dysfunction caused by ischemic insults through AMPK signal pathway- not only shifts metabolism. Toxicol Sci :|