Abstract
Hydroxytyrosol acetate (HT-AC), a natural polyphenolic compound in olive oil, exerts an anti-inflammatory effect in cardiovascular diseases (CVDs). Pyroptosis is a newly discovered form of programmed inflammatory cell death and is suggested to be involved in the atherosclerosis (AS) process. However, the effect of HT-AC on vascular endothelial cell pyroptosis remains unknown. Thus, we aimed to investigate the effect of HT-AC on vascular endothelial cell pyroptosis in AS and related signaling pathways. In vivo studies showed that HT-AC alleviated the formation of atherosclerotic lesions and inhibited pyroptosis in the aortic intima of ApoE−/− mice fed a high-fat diet (HFD) for 12 weeks. In vitro, we found that HT-AC treatment of human umbilical vein endothelial cells (HUVECs) alleviated tumor necrosis factor-alpha (TNF-α)-induced pyroptosis by decreasing the number of PI positive cells, decreasing the enhanced protein expressions of activated caspase-1 and gasdermin D (GSDMD), as well as by decreasing the release of pro-inflammatory interleukin (IL)-1β and IL-6. Besides, HT-AC down-regulated HDAC11 expression in the aortic intima of HFD-fed ApoE−/− mice and TNF-α-stimulated HUVECs. To determine the underlying mechanism of action, molecular docking and drug affinity responsive target stability (DARTS) were utilized to identify whether HDAC11 protein is a target of HT-AC. The molecular docking result showed good compatibility between HT-AC and HDAC11. DARTS study's result showed that HDAC11 protein may be a target of HT-AC. Further study demonstrated that knockdown of HDAC11 augmented the inhibition of HT-AC on pyroptosis in TNF-α-stimulated HUVECs. These findings indicate that HT-AC might prevent vascular endothelial pyroptosis through down-regulation of HDAC11 related signaling pathway in AS.
Highlights
Atherosclerosis (AS) is a chronic inflammatory disease that is initiated by endothelial dysfunction and structural alterations and involves chronic inflammation of the vascular wall (Weber and Noels, 2011)
Our results showed that severe atherosclerosis was successfully induced in our model, while 12 weeks of Hydroxytyrosol acetate (HT-AC) treatment decreased the lipid deposition(Figure 1A) and plaque formation in ApoE−/− mice fed with high-fat diet (HFD) (Figures 1B,C)
Western blotting results further showed that the protein expressions of cleaved caspase-1, gasdermin D (GSDMD) and GSDMD-N in the thoracic aorta of HFD-fed ApoE−/− mice were significantly increased as compared with the normal diet (ND) group, while HT-AC significantly suppressed the enhanced protein expressions of cleaved caspase-1, GSDMD and GSDMD-N (Figures 2B-E)
Summary
Atherosclerosis (AS) is a chronic inflammatory disease that is initiated by endothelial dysfunction and structural alterations and involves chronic inflammation of the vascular wall (Weber and Noels, 2011). Previous studies have shown that endothelial cell death is a crucial and initial stage in the process of AS (Wu et al, 2018; Xing et al, 2020). Olive oil phenolic compounds can be used to prevent and treat cardiovascular diseases (CVDs) (Bulotta et al, 2014). Since pyroptosis is involved in the inflammatory process of AS (Chang et al, 2013), we hypothesize that HT-AC might play a role in inflammation by regulating pyroptosis in endothelial cells.
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