18 beta-Glycyrrhetinic Acid Ameliorates Endoplasmic Reticulum Stress-Induced Inflammation in Pulmonary Arterial Hypertension through PERK/eIF2 alpha/NF-kappa B Signaling

Endoplasmic reticulum stress (ERS)-induced inflammation participates in the occurrence of pulmonary arterial hypertension (PAH) by promoting pulmonary vascular remodeling, which involved in the activation of PERK/eIF2 alpha/NF-kappa B signaling pathway. 18 beta-Glycyrrhetinic acid (18 beta-GA) has been found efficacious for attenuating PAH through its anti-remodeling effects in our previous research and it remains unclear whether 18 beta-GA has an effect on the remodeling caused by ERS-induced inflammation. In this study, we made observations in monocrotaline-induced PAH rats and found improvement of hemodynamic and histopathological parameters, decreases in the right ventricular hypertrophy index, and alleviation of pulmonary vascular remodeling after 18 beta-GA administration in vivo. Moreover, 18 beta-GA could significantly inhibit the proliferation and DNA synthesis of human pulmonary arterial smooth muscle cells (HPASMCs) induced by platelet-derived growth factor BB. At the cellular and molecular levels, we found that 18 beta-GA could significantly reduce the accumulation of misfolded protein in rat lung tissue, inhibit ERS activation, reduce the expression of GRP78, p-PERK, p-eIF2 alpha, and p-NF-kappa B p65, and increase I kappa B protein expression. 18 beta-GA could inhibit the migration of NF-kappa B into the nucleus, reduce the contents of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and monocyte chemoattractant protein-1 (MCP-1) in the culture supernatant of HPASMCs, and reduce GRP78, p-PERK, p-eIF2 alpha, p-NF-kappa B p65, TNF-alpha, IL-6, and MCP-1 protein expression, increase I kappa B protein expression in HPASMCs. According to what we observed, this study indicated that 18 beta-GA could treat PAH, which is related to the inhibition of PERK/eIF2 alpha/NF-kappa B signaling pathway.