Tanshinone IIA Protects Ischemia/Reperfusion-Induced Cardiomyocyte Injury by Inhibiting the HAS2/FGF9 Axis.

Abstract

Purpose: This study aimed to investigate the impacts of tanshinone IIA (Tan IIA) on ischemia/reperfusion (I/R)-induced cardiomyocyte injury in coronary heart disease (CHD), and to determine whether Tan IIA regulates myocardial cell injury induced by I/R through the Hyaluronan Synthase 2/fibroblast growth factor 9 (HAS2/FGF9) axis.

Methods: Weighted gene co-expression network analysis (WGCNA) of the GSE23561 microarray dataset determined gene modules linked to CHD. The key genes were further explored through differential expression and protein-protein interaction (PPI) network analyses. Human AC16 cardiomyocytes were treated with Tan IIA, HAS2 knockdown, and FGF9 overexpression and they were exposed to normoxic, hypoxic, and I/R environments. Cell viability, apoptosis, gene/protein expression, and markers of oxidative stress were evaluated in vitro.

Results: The turquoise module was significantly correlated with CHD and HAS2 was identified as a hub gene. Under hypoxic conditions, Tan IIA exhibited a dose-dependent cardioprotective effect. Tan IIA ameliorated I/R-induced cellular injury, as evidenced by increased cell viability, decreased apoptosis, and regulation of key proteins (PCNA, Bax). After I/R conditions, knockdown of HAS2 increased cell viability and reduced apoptosis, whereas overexpression of FGF9 reversed these effects. Notably, HAS2 knockdown also ameliorated I/R-induced increases in inflammatory cytokines and oxidative stress, and synergistic protection was provided by combined treatment with FGF9 and Tan IIA.

Conclusion: Taken together, our findings confirm that Tan IIA protects cardiomyocytes from I/R-induced injury by controlling the HAS2/FGF9 axis. These findings reveal the potential therapeutic significance of Tan IIA in alleviating CHD-related myocardial dysfunction.