4-phenylbutyrate and valproate treatment attenuates the progression of atherosclerosis and stabilizes existing plaques

4‐Phenylbutyrate protects against atherosclerotic lesion growth by increasing the expression of HSP25 in macrophages and in the circulation of Apoe −/− mice

“…A similar observation was reported by Liao et al (30) in a mouse model of hyperhomocysteinemia in which hyperhomocysteinemic mice exhibited increased total cholesterol and decreased ApoA1, as well as alterations to lipoprotein particle size and lipid content, without affecting the number of HDL particles. The lipid parameters observed in the current study differ from previous reports in which 4-PBA treatment did not result in significant differences in plasma lipids or glucose levels in either Apoe 2/2 or LDLR 2/2 high-fat-fed mice (10)(11)(12). These discrepancies may be attributed to differences in the diet used (chow vs. high-fat diet), or in part to differences in the ages at which mice were assessed in previous studies since lesions were evaluated at earlier time points than those used in our current study.…”

“…Water consumption and weight gain were monitored in order to ensure treated groups received a 4-PBA dose of 1 or 2.5 g/kg/d. Previous studies have reported the beneficial effect of 4-PBA on lesion size in the context of high-fat feeding (10)(11)(12). In the current study, by using a chow diet, we aimed to determine whether 4-PBA exhibited an inhibitory effect on lesion growth in Apoe 2/2 mice in the absence of confounding factors associated with high-fat diets such as insulin resistance and obesity (29).…”

“…Previous reports have independently shown the protective effects of both 4-PBA and HSP27 on lesion progression and atherosclerosis, describing potential roles in multiple pathways, such as monocyte-macrophage infiltration and apoptosis, that contribute to atherogenesis (10,11,14,17,18,32). To examine the potential link between 4-PBA and HSP27, we treated THP-1 macrophages with 4-PBA for 24 h and assessed its effect on nuclear localization of HSF1, the major transcription factor that modulates HSP27 expression (33), using immunofluorescence staining (Fig.…”

“…Such an effect was also observed in a subsequent study (12) in which 16-wkold male Apoe 2/2 mice fed a high-fat diet (8 wk) exhibited smaller lesions when treated with 4-PBA (5 wk; intraperitoneally every 3 d). High-fat-fed (10 wk) LDL receptor (LDLR) 2/2 mice given 4-PBA in their drinking water also exhibited smaller lesion sizes at 14 wk of age (11). Although these studies provide evidence that 4-PBA treatment via multiple routes (intraperitoneal injection, orally, and in addition to the drinking water) reduces lesion size, the underlying mechanisms by which 4-PBA contributes to this protection have not been completely defined.…”

“…4-Phenylbutyrate (4-PBA) is a small chemical chaperone that has been shown to alleviate ER stress and reduce atherosclerotic lesion growth in high-fat-fed mice (10)(11)(12). As expected with 4-PBA treatment (2 wk; oral, daily), a previous study observed reduced expression of ER stress markers [phosphorylated (P)-protein kinase-like ER kinase (PERK), P-eukaryotic translation initiation factor 2A, and CHOP], as well as smaller lesions, in 14-wk-old Apoe 2/2 mice fed a high-fat diet (8 wk) (10).…”