Therapeutic Effects of Retinoic Acid in Lipopolysaccharide-Induced Cardiac Dysfunction: Network Pharmacology and Experimental Validation

Xi Wang; Chang Kong; Pan Liu; Baofeng Zhou; Wujun Geng; Hongli Tang

doi:10.2147/JIR.S358374

Therapeutic Effects of Retinoic Acid in Lipopolysaccharide-Induced Cardiac Dysfunction: Network Pharmacology and Experimental Validation

J Inflamm Res. 2022 Aug 30:15:4963-4979. doi: 10.2147/JIR.S358374. eCollection 2022.

Authors

Xi Wang^#^{1

2}, Chang Kong^#^{1

3}, Pan Liu^{1

2}, Baofeng Zhou^{1

2}, Wujun Geng^{1

2}, Hongli Tang^{1

2}

Affiliations

¹ Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.
² Wenzhou Key Laboratory of Perioperative Medicine, Wenzhou, People's Republic of China.
³ Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Sepsis, which is deemed as a systemic inflammation reaction syndrome in the face of infectious stimuli, is the primary cause of death in ICUs. Sepsis-induced cardiomyopathy (SIC) may derive from systemic inflammation reaction and oxidative stress. Retinoic acid (RA) is recognized by its beneficial roles in terms of the immunoresponse to infections and antioxygen actions. However, the treatment efficacy and potential causal links of RA in SIC are still elusive.

Methods: By virtue of the STITCH database, we identified the targets of RA. Differentially expressed genes in SIC were acquired from the GEO database. The PPI network of intersected targets was established. GO and KEGG pathway enrichment analysis was completed. Hub genes were analyzed by cytoHubba plug-in. In the process of experimental validation, a mouse sepsis model was established by lipopolysaccharide (LPS), and the treated mice were intraperitoneally injected with RA or Dexamethasone (DEX) 60 min prior to LPS injections. Survival conditions, cardiac functions and antioxidant levels of the mice were assessed. Cardiac inflammation and injury were detected by HE and TUNEL. The levels of key genes and signal pathway expression were analyzed by RT-PCR and Western blot.

Results: PPARA, ITGAM, VCAM-1, IGF-1 and IL-6 were identified as key therapeutic targets of RA by network pharmacology. PI3K-Akt signaling pathway is the main regulatory pathway of RA. In vivo researches unraveled that RA can improve the survival rate and cardiac function of LPS-treated mice, inhibit inflammatory factors and myocardial injury, and regulate the expression of key therapeutic targets and key pathways, which is PI3K-Akt signaling pathway.

Conclusion: Network pharmacological method offers a predicative strategy to explore the treatment efficacy and causal links of RA in endotoxemic myocarditis. Through experimental verification, we discover that RA can reduce lipopolysaccharide-induced cardiac dysfunction by regulating the PI3K-Akt signaling pathway and key genes.

Keywords: inflammatory response; lipopolysaccharide; network pharmacology; retinoic acid; sepsis-induced cardiomyopathy.

Grants and funding

We acknowledge the funding received from the Natural Science Foundation of China (Grant No. 81774109 and 81973620) and Wenzhou Municipal Science and Technology Bureau (ZY2019015).