Rosuvastatin protects against endothelial cell apoptosis in vitro and alleviates atherosclerosis in ApoE‑/‑ mice by suppressing endoplasmic reticulum stress

Abstract

The development of abnormal lipid-induced atherosclerosis is initiated with endothelial cell apoptosis. Vascular endothelial cells possess highly developed endoplasmic reticulum (ER), which is involved in lipid metabolism, indicating that ER stress may contribute chiefly to the induction of endothelial cell apoptosis. Based on its ability to reduce cholesterol levels, rosuvastatin may play an endothelial and vascular protective role by regulating ER stress. In the present study, the involvement of the inhibition of the ER stress-induced endothelial injury was investigated in combination with the lipid lowering effects of rosuvastatin. This compound can be used to inhibit cholesterol synthesis in atherosclerosis. Rosuvastatin decreased the apoptotic rates of human umbilical vascular endothelial cells (HUVECs) that had been stimulated with ox-low density lipoprotein (LDL) in vitro and repressed the mRNA levels of CHOP, sXBP1 and caspase-12, and decreased caspase-12 activity, as well as the content of glucose-regulated protein 78 (GRP78), phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-inositol-requiring protein 1α (IRE1α) and p-eIF2α proteins. In addition, ApoE-/mice were fed with atherogenic chow for 8 weeks for atherosclerosis induction and rosuvastatin was provided by intragastric administration for an additional 4 weeks. Subsequently, the atherosclerotic plaque formation in the aorta was evaluated by Oil Red O and hematoxylin and eosin staining, and the serum LDL, high-density lipoprotein, total cholesterol (TC) and triacylglycerol (TG) levels were measured. In addition, the induction of apoptosis of endothelial cells and the expression levels of GRP78, p-PERK, p-IRE1α and p-eIF2α were assessed in the aorta. Rosuvastatin repressed atherosclerotic plaque formation and endothelial apoptosis in the aorta and decreased LDL and TG levels in the serum, as determined by in vivo results. Furthermore, it downregulated the expression levels of protein chaperone GRP78, p-PERK, p-IRE1α and p-eIF2α in the aortic intima. The data indicated that rosuvastatin could protect HUVECs from ER stress-induced apoptosis triggered by oxidized LDL. It could also inhibit atherosclerosis formation in ApoE-/mice aorta by regulating the PERK/eIF2α/C/EBPα-homologous protein and IRE1α/sXBP1 signaling pathways. Taken collectively, the present study demonstrated the preventive and therapeutic effects of rosuvastatin in protecting from the development of endothelial cell dysfunction diseases.

A comparison of the effects of monotherapy with rosuvastatin, atorvastatin or ezetimibe versus combination treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe on the integrity of vascular endothelial cells damaged by oxidized cholesterol

“…Although no such effect was observed at a concentration of 0.7 μM (391 ng/mL), it was found that cell viability was decreased and necrosis increased at 7, 35 and 70 μM (3910, 19 551 and 39 102 ng/mL). Literature data not only confirms that rosuvastatin does not induce apoptosis, but also it has a protective effect on HUVEC stimulated with ox-LDL (200 μg/mL) at concentrations of 0.01, 0.1 and 1 μM (4.8, 4.82 and 481.5 ng/mL) [ 13 ]. Similarly, Qin et al .…”

Clinical study of different doses of atorvastatin combined with febuxostat in patients with gout and carotid atherosclerosis

“…Several studies have shown that atorvastatin can affect the expression of nuclear factor κB, TLR4 and its downstream signals and MMP-9, inhibit inflammatory reactions and stabilize atherosclerotic plaques in various ways. 20,22 The results showed that TNF-α, IL-1β, CRP and other inflammatory indexes in the treatment group were significantly lower than those in the control group. Atherosclerotic plaque area decreased, indicating that double doses of atorvastatin combined with febuxostat can better reduce inflammatory reactions in patients with gout and carotid atherosclerosis.…”

Exosomal miR-129 and miR-342 derived from intermittent hypoxia-stimulated vascular smooth muscle cells inhibit the eIF2α/ATF4 axis from preventing calcified aortic valvular disease

“…Previous studies have revealed the involvement of ATF4 and eIF2α in CAVD and its related disorders. Downregulation of the PERK/eIF2α/C/EBPα signaling is unveiled to suppress the formation of atherosclerosis in the aorta of ApoE knockout mice (Geng et al 2020). Silencing of ATF4 was also reported to regulate osteoblastic differentiation in VICs, which limited aortic valve calcification (Fu et al 2019).…”