Abstract
As a major bioactive compound from grapes, piceatannol (PIC) has been reported to exert anti-atherosclerotic activity in various studies. Nevertheless, the mechanism underlying the effect of piceatannol against atherosclerosis (AS) is elusive. Our study identified miR-200a/Nrf2/GSDMD signaling pathway as critical mediators in the effect of piceatannol on macrophages. In the present study, we confirmed that treatment of piceatannol repressed the oxLDL-induced lipid storage in macrophages. Compared with control group, piceatannol inhibited TG storage and the activity of caspase1. It is noting that in response to oxLDL challenge, piceatannol abated the pyroptosis in RAW264.7 cells, with a decreased expression of caspase1, gasdermin D (GSDMD), IL-18, IL-1β and NLRP3. Moreover, we investigated the role of microRNA (miR)-200a/Nrf2 signaling pathway in the effect of piceatannol. The results declared that after transfection of si-miR-200a or si-Nrf2 plasmids, the effects of piceatannol on macrophages were converted, including lipid storage and pyroptosis. Importantly, si-miR-200a plasmid reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), indicating that miR-200a acted as an enhancer of Nrf2 in macrophages. Collectively, our findings demonstrate that piceatannol exerts anti-atherosclerotic activity on RAW264.7 cells by regulating miR-200a/Nrf2/GSDMD signaling. The present study is the first time to identify miR-200a as a candidate target in AS and declared an association between miR-200a and pyroptosis, which provides a novel therapy for the treatment of AS.
Highlights
As a chronic vascular disease, atherosclerosis (AS) is currently seriously affecting human health
We found that piceatannol attenuated the lipid accumulation in macrophages in response to oxLDL challenge, which was associated with decreased level of pyroptosis
To determine the effect of PIC (Figure 1A) on oxLDL-induced lipid storage in macrophages, macrophages RAW264.7 were treated with oxLDL (80 mg/l) for 24 h in the absence or presence of PIC (30 μM)
Summary
As a chronic vascular disease, atherosclerosis (AS) is currently seriously affecting human health. In the progression of AS, the formation of plaque necrosis is promoted by the death of lesional macrophages and defective phagocytic clearance of the dead cells [2]. Pyroptosis is a highly inflammatory programmed cell death and an important form of innate immune response during infections and tissue damages [3,4]. Previous studies suggest that pyroptosis plays an important role in advanced lesional macrophage death. In the process of macrophage death, two signals were required to up-regulate pro-IL-1β and to induce NLRP3-mediated maturation of IL-1β [5]. Interaction of NLRP3 with ASC recruits pro-CASP1, and cleaves and releases mature IL-1β via pores formed by gasdermin D (GSDMD) [6]
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