Persistence of Western Diet-Associated Pathway Activity Profiles in Ventricular Tissues

The consumption of a Western diet (WD), characterized by high levels of fats and sugars, is strongly associated with adverse cardiovascular outcomes. In this case-control study, we evaluated long-term alterations in signaling pathway activities in the left (LV) and right (RV) ventricular tissues of C57Bl/6J mice that were exposed to WD starting at 300 days of age for 125 days before switching to a normal diet (ND). LV and RV tissues were collected at 530 days and subjected to RNA sequencing. Pathway activity for 40 signaling pathways (comprising 709 pathway branches/sinks) was calculated using the topology-aware Pathway Signal Flow (PSF) algorithm, which assesses signal propagation along a pathway based on gene expression levels of its components and their interactions. We observed significant perturbations in 14 pathway branches specifically in LV tissue of male mice, 105 days after the ND switch. These alterations included the downregulation of cardioprotective VEGF signaling and the upregulation of pro-fibrotic TGF-beta signaling, suggesting lasting cardiovascular risks. Furthermore, strong signaling was detected in the cGMP-PKG and FOXO pathways linked to cardiac failure. Finally, pro- and anti-apoptotic signals were simultaneously upregulated, accompanied by the downregulation of cell cycle inhibitors. Notably, no significant gene expression changes were detected in the left ventricular tissue of females, and no significant differences were observed in right ventricular tissue in either sex. These findings suggest that the effects of a Western diet may persist even after transitioning to a healthier diet. Further studies are needed to elucidate the diet-associated risks and develop strategies to mitigate these long-term effects.