Varinostat alters gene expression profiles in aortic tissues from ApoE-/- mice.

BACKGROUND: Atherosclerosis (AS) is a complex, chronic inflammatory disease that is characterized by plaque build-up within arterial vessel walls. Preclinical trials have suggested that vorinostat, a pan-histone deacetylase inhibitor (HDACi), reduces vascular inflammation and AS, but the underlying protective mechanism has not been fully elucidated. The present study aimed to identify altered gene expression profiles in aortic tissues from ApoE-/- mice after vorinostat treatment.

METHODS: Male ApoE-/- mice fed a high fat diet were treated with either vorinostat or vehicle and aortic plaque area was quantified 8 weeks after treatment. Aortic tissues were collected from both the vorinostat group (n = 3) and vehicle group (n = 3) for deep sequencing of the cDNA to construct sRNA libraries.

RESULTS: Oral administration of vorinostat significantly reduced plaque size in the ApoE-/- mice (p < 0.05). In total, 1,550 differentially expressed mRNAs, 56 differentially expressed miRNAs, and 381 differentially expressed lncRNAs were identified in the vorinostat group compared to the vehicle group. Subsequently, we constructed a global lncRNA-miRNA-mRNA triple network based on the competitive endogenous RNA (ceRNA) theory. The Hepatitis C signaling pathway was significantly enriched among the differentially expressed mRNAs from the ceRNA network, which suggests that vorinostat has anti-inflammatory properties. Importantly, the identified target pair of mmu-miR-3075-5p/lncRNA-A330023F24Rik/Ldlr may regulate drug response. Up-regulation of low density lipid receptor (Ldlr) and lncRNA-A330023F24Rik and down-regulation of mmu-miR-3075-5p were further verified by qRT-PCR.

CONCLUSION: Vorinostat reduces AS in ApoE-/- mice. We identified differentially expressed mRNA, lncRNAs, and miRNAs, as well as their interactions and pathways, which partially explain vorinostat's anti-atherosclerotic effects.