Effects of cyclophilin A inhibition by cyclosporine and 4MCsA on gene expression of innominate arteries from high fat diet-induced Ldlr-/- mice

Cyclophilin A (CypA) has been increasingly recognized as one of the key factors in the pathogenesis of atherosclerosis. Here we have used extracellular CypA (eCypA) inhibitor 4MCsA and non-selective CypA inhibitor cyclosporine (CsA) to modulate the activity of CypA, thus revealing the eCypA-mediated signaling pathways in Ldlr-/- mice. We performed RNA-seq analysis of innominate arteries, which is one of the most preferred sites for lesion development in mice. KEGG pathway enrichment analysis revealed that thermogenesis, oxidative phosphorylation, PPAR signaling pathway, fatty acid degradation and metabolism signaling pathways were markedly correlated with the phenotype induced by 4MCsA administration. In addition, 4MCsA treatment observably downregulated the genes enriched in inflammation and oxidative stress pathways, including Cebpd, Adamts1, Adamts4, Adamts8, Adamts9 and Hmox1. Interestingly, both lipid metabolism (including lipolysis and fatty acid oxidation) and inflammation are closely associated with PPAR signaling activation. Taken together, these data indicated that 4MCsA treatment improved atherosclerosis via upregulating lipid metabolism- and downregulating inflammation-related pathways downstream of PPAR signaling.