COX-2 as the key target of LianXia NingXin Formula for treating Sympathetic Remodeling after Myocardial Infarction: pharmacological network prediction with experimental validation

Ethnopharmacological relevance: Previous studies have shown that LianXia NingXin (LXNX) formula, a Chinese herbal prescription, can prevent the sympathetic remodeling after myocardial infarction (MI). It is absolutely necessary to further investigate the pharmacological mechanism of action for LXNX formula to treat sympathetic remodeling after MI occurs. Material and methods: In this study, the most important protein target of LXNX formula to prevent sympathetic remodeling was identified by ranking the number of influencing ingredients (degree) of those targets in this network and how strong those targets had influence on sympathetic remodeling. Next, preclinical research was conducted on MI rat models treated with LXNX formula and celecoxib to verify this predicted pharmacological results. Celecoxib is a modern drug known to inhibit the target predicted through the method of the network analysis. After thirty day treatment, the protein and mRNA expression of this predicted protein in the peri-infarct zone of rats was measured. Results: The results of pharmacological network analysis showed that Cyclooxygenase-2 (COX-2) was predicted as the most important drug target of LXNX formula to treat sympathetic remodeling. Preclinical research indicated that both LXNX formula and celecoxib significantly reduced distribution of sympathetic remodeling around the peri-infarct zone of rats in pre-clinical research; also, the levels of COX-2 protein and its gene expression in the myocardium of rats post-MI were significantly decreased by LXNX formula and celecoxib. Related literature evidences demonstrated that LXNX formula is less likely to damage the gastrointestinal mucous membrane because the effects of its ingredients like curcumin and hesperidin to reduce cell apoptosis in the gastrointestinal tract. Conclusion: This study indicated that COX-2 is the key drug target of LXNX formula through which it inhibits adverse sympathetic nerve sprouting after MI.