Depressive disorders induced by acute myocardial infarction (AMI) play a pivotal role in the deterioration of cardiac function, and Shuangxinfang (Psycho-cardiology Formula, PCF) was reported to alleviate heart function damage and improve depression-like behavior, but the complex mechanism in such process has not been clarified.

AMI models were established and PCF was administered in rats. Subjects were then assessed in open field test (OFT) and forced swimming test (FST) recapitulating symptoms of depressive disorder. Afterward, pharmacoproteomic profiling of the hippocampus and peri-infarct border zone (BZ) was performed using a label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique, to identify contributing proteins and pathways responsible for myocardial ischemia and behavioral allostasis. Bioinformatics analysis was processed for further investigation, while western blotting was employed for testing dominating proteins to validate proteomic results.

Rats in the AMI group showed depression-like behavior in OFT and FST, which was improved by PCF. There were 131 differentially expressed proteins (DEPs) in BZ and 64 proteins in the hippocampus being detected and quantified shared by the sham group, the AMI group, and the PCF group. Subsequently, pertinent pathways and molecular functions were further identified. Altered molecules were discovered to be enriched in the apoptotic process, innate immune response, and NF-κB transcription factor activity in BZ, as well as chemical synaptic transmission, axon, collagen binding, cell adhesion, response to carbohydrate, laminin binding, and cellular response to nitric oxide in the hippocampus. Groups of signal transducers were also able to select multiple pathways, including innate immunity and arginine biosynthesis in the heart, also integrin signaling in the brain. DEPs were intersected from the myocardium and hippocampus to screen out the protein S100A9, which was up-regulated in the AMI group compared with the sham, and showed a down-regulation trend after treatment with PCF.

Taken together, we present a comprehensive proteomics analysis of rat models with depression post-AMI. Reviewing the literatures concerned, it’s hypothesized that macrophage/microglia inflammation mediated by S100A9 might be the pivotal pathogenic process of psycho-cardiology disease, as well as potential mechanisms for the treatment of PCF.