Abstract
There is a growing body of evidence that excess lipids, hypoxic stress and other inflammatory signals can stimulate endoplasmic reticulum (ER) stress in metabolic diseases. However, the pathophysiological importance and the underlying mechanisms of this phenomenon remain unknown. The current study investigated that 50 ng/ml oxidized LDL promoted unfolded protein response (UPR) and ER stress in J774A1 murine macrophages, which was blocked by extracts (PPE) of purple Perilla frutescens, a plant of the mint family Lamiaceae. The ER stressor tunicamycin was employed as a positive control. Treating 1–10 µg/ml oxidized LDL for 24 h elicited lipotoxic apoptosis in macrophages with obvious nuclear condensation and DNA fragmentation, which was inhibited by PPE. Tunicamycin and oxidized LDL activated and induced the UPR components of activating transcription factor 6 and ER resident chaperone BiP/Grp78 in temporal manners and such effects were blocked by ≥5 µg/ml PPE. In addition, PPE suppressed the enhanced mRNA transcription and splicing of X-box binding protein 1 (XBP1) by tunicamycin and oxidized LDL. The protein induction and nuclear translocation of XBP1 were deterred in PPE-treated macrophages under ER stress. The induction of ATP-binding cassette transporter A1 (ABCA1), scavenger receptor-B1 (SR-B1) and intracellular adhesion molecule-1 (ICAM-1) was abolished by the ER stressor in activated macrophages. The protein induction of ABCA1 and ICAM1 but not SR-B1 was retrieved by adding 10 µg/ml PPE to cells. These results demonstrate that PPE inhibited lipotoxic apoptosis and demoted the induction and activation of UPR components in macrophages. PPE restored normal proteostasis in activated macrophages oxidized LDL. Therefore, PPE was a potent agent antagonizing macrophage ER stress due to lipotoxic signals associated with atherosclerosis.
Highlights
An accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen causes a cellular ER stress initiating unfolded protein response (UPR) [1]
The DNA laddering was obvious in tunicamycin-exposed macrophages, which was blunted by purple perilla frutescens leaf extract (PPE) (Figure 1C)
Tunicamycin-induced ER stress caused nuclear condensation and fragmentation of macrophages, while such condensation and fragmentation disappeared in 10 mg/ ml PPE-treated cells, evidenced by Hoechst 33258 staining and transferase dUTP nick end labeling (TUNEL) (Figure 1D)
Summary
An accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen causes a cellular ER stress initiating unfolded protein response (UPR) [1]. The UPR functions in order to primarily restore normal proteostasis in the ER by halting protein translation and activating the signaling pathways leading to the production of molecular chaperones involved in protein folding [2]. The UPR instigates cell survival by improving protein folding capacity of ER, or promotes cell death following chronic ER stress [3]. Excessive activation of sustained UPR results in cellular dysfunction and cell death as major contributors to cancer and neurodegenerative diseases [4,5]. Unresolved ER stress is involved in a variety of metabolic disorders, such as obesity and type 2 diabetes mellitus [6]
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