Abstract
BackgroundEndoplasmic reticulum (ER) stress has been implicated in the pathophysiology of various pulmonary diseases via the activation of the unfolded protein response. However, the role of ER stress in pulmonary arterial hypertension (PAH) remains unclear. The well-known chemical chaperone 4-phenylbutyric acid (4-PBA) inhibits ER stress signaling. We hypothesized that known chemical chaperones, including 4-PBA, would inhibit the activation of ER stress and prevent and/or reverse PAH.Methods and ResultsMale Wistar rats were randomly divided into four groups: a normal control group (NORMAL group), a PAH group, and two PAH model plus 4-PBA treatment groups. The latter two groups included rats receiving 4-PBA by gavage each day as a preventive measure (the PRE group, with PBA starting on the day of PAH induction and continuing for 4 weeks) or as a reversal measure (the REV group, with PBA starting on the third week of PAH induction and continuing for 2 weeks). The PAH model was induced by intraperitoneally administering monocrotaline. The mean pulmonary artery pressure and mean right ventricular pressure were lower in the REV and PRE groups than in the NORMAL group. Furthermore, 4-PBA improved pulmonary arterial remodeling and suppressed the expression of ER stress indicators.ConclusionOur findings indicate that PAH induces ER stress and provokes pulmonary arterial and right ventricular remodeling. Additionally, we show that attenuation of ER stress has the potential to be an effective therapeutic strategy for protecting pulmonary arteries.
Highlights
Pulmonary arterial hypertension (PAH) is a refractory syndrome that causes restricted flow through the pulmonary arterial circulation
Male Wistar rats were randomly divided into four groups: a normal control group (NORMAL group), a PAH group, and two PAH model plus 4-phenylbutyric acid (4-PBA) treatment groups
The latter two groups included rats receiving 4-PBA by gavage each day as a preventive measure or as a reversal measure
Summary
Pulmonary arterial hypertension (PAH) is a refractory syndrome that causes restricted flow through the pulmonary arterial circulation. PAH can be associated with many conditions, including BMPR2 mutation, connective tissue diseases, portal hypertension, congenital heart disease and schistosomiasis. PAH is characterized by pulmonary vascular remodeling, including pulmonary artery smooth muscle cell (PASMC) proliferation, micro-thrombosis, and sustained pulmonary vasoconstriction. These conditions lead to increased pulmonary arterial pressure, right ventricular failure, and death [2]. Multiple pathogenic pathways have been implicated in the development of PAH, but their mechanisms remain unclear [3]. The role of ER stress in pulmonary arterial hypertension (PAH) remains unclear. The well-known chemical chaperone 4-phenylbutyric acid (4-PBA) inhibits ER stress signaling. We hypothesized that known chemical chaperones, including 4-PBA, would inhibit the activation of ER stress and prevent and/or reverse PAH
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