HDAC3 protects against atherosclerosis through inhibition of inflammation via the microRNA-19b/PPARγ/NF-κB axis

Background and aims: Atherosclerosis (AS) is one of the leading causes of cardiovascular diseases. Studies have revealed critical roles of microRNAs (miRNAs) in the progression of AS. This study was conducted to elucidate the role and mechanism by which miR-19b influences AS. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low-density lipoprotein (ox-LDL), and an AS mouse model was generated with the help of ApoE-/- mice using a high-fat diet regimen. The expression patterns of peroxisome proliferator-activated receptor ? (PPAR?), nuclear factor ?B (NF-?B)/p65, miR-19b and histone deacetylase 3 (HDAC3) were then characterized by reverse transcription quantitative polymerase chain reaction and Western blot analysis. In addition, the relationship among PPAR?, NF-?B/p65, miR19b and HDAC3 was evaluated by co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter gene assays. Gain- and loss-of-function experiments were also performed to examine their functional significance on ox-LDL-induced inflammation in HUVECs. Enzyme-linked immunosorbent assay was applied to determine the expression patterns of inflammatory factors in AS mice. Results: PPAR? and HDAC3 were poorly expressed, while miR-19b and NF-?B/p65 were highly expressed in oxLDL-induced HUVECs and arterial tissues of AS mice. PPAR? inhibited ox-LDL-induced inflammation in HUVECs by ubiquitination and degradation of NF-?B/p65. miR-19b, downregulated by HDAC3, targeted PPAR? and negatively-regulated its expression. Upregulated PPAR? or HDAC3 or downregulated miR-19b or NF-?B/p65 reduced TNF-? and IL-1? expression levels in ox-LDL-induced HUVECs and AS mice. Conclusions: Collectively, the results show that HDAC3 upregulation prevents inflammation to inhibit AS by inactivating NF-?B/p65 via upregulation of miR-19b-mediated PPAR?, providing a basic therapeutic consideration for AS treatment.

Automated summary

This study elucidated the role of miR-19b in atherosclerosis, showing that it regulates AS development by modulating PPAR?, NF-?B/p65, and HDAC3 expression levels. This provides a fundamental basis for potential AS treatment strategies.