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

Abstract

Endoplasmic reticulum stress plays an important role in cardiovascular disease (CVD) and atherosclerosis. We aimed to assess the ability of 4‐phenylbutyrate (4‐PBA), a small chemical chaperone administered via drinking water, to reduce atherosclerotic lesion size in chow‐fed apolipoprotein (Apo) e−/− mice and to identify mechanisms that contribute to its antiatherogenic effect. Chow‐fed 17‐wk‐old female Apoe−/− mice treated with 4‐PBA–supplemented drinking water for 5 wk exhibited smaller lesions as well as increased plasma levels of heat shock protein (HSP) 25, the mouse homolog of human HSP27, compared with controls. In addition, 4‐PBA inhibited cell death and increased HSP27 expression as measured by real‐time PCR and immunoblotting, as well as induced nuclear localization of its transcription factor, heat shock factor 1, in human monocyte/macrophage (THP‐1) cells. Furthermore, HSP27 small interfering RNA diminished the protective effect of 4‐PBA on THP‐1 macrophage attachment and differentiation. In summary, drinking water containing 4‐PBA attenuated early lesion growth in Apoe−/− mice fed a chow diet and increased expression of HSP25 and HSP27 in macrophages and HSP25 in the circulation of Apoe−/− mice. Given that increased expression of HSP27 is inversely correlated with CVD risk, our findings suggest that 4‐PBA protects against the early stages of atherogenesis in part by enhancing HSP27 levels, leading to inhibition of both macrophage cell death and monocyte‐macrophage differentiation.—Lynn, E. G., Lhoták, Š., Lebeau, P., Byun, J. H., Chen, J., Platko, K., Shi, C., O'Brien, E. R., Austin, R. C. 4‐Phenylbutyrate protects against atherosclerotic lesion growth by increasing the expression of HSP25 in macrophages and in the circulation of Apoe−/− mice. FASEB J. 33, 8406–8422 (2019). http://www.fasebj.org

Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export

“…Our work here establishes that small-molecule inhibition of the secretory pathway may be a useful alternative to inhibit PCSK9 function. Indeed, 4-PBA has been shown to reduce atherosclerosis in mice ( 36 , 37 ), although the molecular basis for this effect is not known. Finally, given the wealth of structural information on cargo selection by SEC24, additional small-molecule screening based on the types of protein–protein interaction assays described here suggests a path forward for more specific inhibition of protein secretion and raises the possibility for systemic modulation of other health-related secretory proteins.…”

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis

“…We initially confirmed that administration of 4-PBA may alleviate atherosclerosis progression in our experimental mouse model. Whereas previous studies administrated 4-PBA through drinking water 19,20 , we elected to treat high-fat diet (HFD)–fed ApoE −/− mice with 4-PBA via intraperitoneal ( i.p. ) injection (100 mg/kg body weight).…”

Selective inhibition of protein secretion by abrogating receptor-coat interactions during ER export

“…Our work here establishes that small-molecule inhibition of the secretory pathway may be a useful alternative to inhibit PCSK9 function. Indeed, 4-PBA has been shown to reduce atherosclerosis in mice (Huang et al , 2017; Lynn et al , 2019), although the molecular basis for this effect was not known. Finally, given the wealth of structural information on cargo selection by SEC24, additional small molecule screening based on the types of protein-protein interaction assays described here suggests a path forward for more specific inhibition of protein secretion, and raises the possibility for systemic modulation other health-related secretory proteins.…”