Restoring perturbed oxylipins with Danqi Tongmai Tablet attenuates acute myocardial infarction

Abstract

Salvianolic acids have a special synergic effect on panax notoginsenosides in acute myocardial infarction (AMI) and have been developed into a new drug as Danqi Tongmai Tablet (DQTT). To explore candidate targets and mechanisms of DQTT on AMI, a network pharmacology-based analysis was performed on absorbed prototype compounds of DQTT in rat plasma. Target prediction from network analysis indicated that the arachidonic acid pathway might contribute to the therapeutic effects of DQTT on AMI, and the regulatory effects on cyclooxygenase (COX) and lipoxygenase (LOX) were validated using an oxygen-glucose deprivation/reoxygenation model established on H9c2 cardiomyocytes. To further explore the action mechanisms of DQTT, 38 oxylipins were quantitatively analyzed among high, medium, and low doses of DQTT using a rat AMI model with an ultra high performance liquid chromatograph coupled with a triple quadrupole mass spectrometry (UHPLC-QqQ/MS) detection system. As attenuation was observed in AMI with DQTT treatment, the perturbed arachidonic acid metabolome was partly restored in a dose-dependent fashion with a significant elevation of anti-inflammatory metabolites, while pro-inflammatory lipids were decreased. Cytokine array analysis also supported the anti-inflammatory effects of DQTT, as significant down-regulation of pro-inflammatory cytokines was observed. The analysis of ischemic heart tissues demonstrated that COX and LOX, the inflammation-induced catalytic enzymes of arachidonic acid metabolism, were inhibited on both gene expression and protein level. These results confirmed that DQTT could restore the arachidonic acid metabolome to maintain an anti-inflammatory profile against the ischemic tissue injury and support that DQTT can be a promising medicinal therapy against AMI.