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
