Intervention of Tanshinone IIA on the PGK1-PDHK1 Pathway to Reprogram Macrophage Phenotype After Myocardial Infarction.

Abstract

Background: Myocardial infarction remains a disease with high morbidity and death rate among cardiovascular diseases. Macrophages are abundant immune cells in the heart. Under different stimulatory factors, macrophages can differentiate into different phenotypes and play a dual pro-inflammatory and anti-inflammatory role. Therefore, a potential strategy for the treatment of myocardial infarction is to regulate the energy metabolism of macrophages and thereby regulate the polarization of macrophages. Tan IIA is an effective liposolubility component extracted from the root of Salvia miltiorrhiza and plays an important role in the treatment of cardiovascular diseases. On this basis, this study proposed whether Tan IIA could affect phenotype changes by regulating energy metabolism of macrophages, and thus exert its potential in the treatment of MI.

Methods: Establishing a myocardial infarction model, Tan IIA was given for 3 days and 7 days for intervention. Cardiac function was detected by echocardiography, and cardiac pathological sections of each group were stained with HE and Masson to observe the inflammatory cell infiltration and fibrosis area after administration. The expression and secretion of inflammatory factors in heart tissue and serum of each group, as well as the proportion of macrophages at the myocardial infarction site, were detected using RT-PCR, ELISA, and immunofluorescence. The mitochondrial function of macrophages was evaluated using JC-1, calcium ion concentration detection, reactive oxygen species detection, and mitochondrial electron microscopic analysis. Mechanically, single-cell transcriptome data mining, cell transcriptome sequencing, and molecular docking technology were used to anchor the target of Tan IIA and enrich the pathways to explore the mechanism of Tan IIA regulating macrophage energy metabolism and phenotype. The target of Tan IIA was further determined by gene knockdown and overexpression assay.

Results: The intervention of Tan IIA can improve the cardiac function, inflammatory cell infiltration and fibrosis after MI, reduce the expression of inflammatory factors in the heart, enhance the secretion of anti-inflammatory factors, increase the proportion of M2-type macrophages, reduce the proportion of M1-type macrophages, and promote tissue repair, suggesting that Tan IIA has pharmacological effects in the treatment of MI. In terms of mechanism, RNA-seq results suggest that the phenotype of macrophages is strongly correlated with energy metabolism, and Tan IIA can regulate the PGK1-PDHK1 signaling pathway, change the energy metabolism mode of macrophages, and then affect its phenotype.

Conclusion: Tan IIA regulates the energy metabolism of macrophages and changes its phenotype through the PGK1-PDHK1 signaling pathway, thus playing a role in improving MI.