Statins Prevent Dextrose-Induced Endoplasmic Reticulum Stress and Oxidative Stress in Endothelial and HepG2 Cells.

Statins have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. However, antioxidant vitamins, unlike statins, are not as cardioprotective, and this paradox has been explained by failure of vitamin antioxidants to ameliorate endoplasmic reticulum (ER) stress. To determine whether statins prevent dextrose-induced ER stress in addition to their antioxidative effects, human umbilical vein endothelial cells and HepG2 hepatocytes were treated with 27.5 mM dextrose in the presence of simvastatin (lipophilic statin that is a prodrug) and pravastatin (water-soluble active drug), and oxidative stress, ER stress, and cell death were measured. Superoxide generation was measured using 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride. ER stress was measured using the placental alkaline phosphatase assay and Western blot of glucose-regulated protein 75, c-jun-N-terminal kinase, phospho-JNK, eukaryotic initiating factor 2α and phospho-eIF2α, and X-box binding protein 1 mRNA splicing. Cell viability was measured by propidium iodide staining. Superoxide anion production, ER stress, and cell death induced by 27.5 mM dextrose were inhibited by therapeutic concentrations of simvastatin and pravastatin. The salutary effects of statins on endothelial cells in reducing both ER stress and oxidative stress observed with pravastatin and the prodrug simvastatin suggest that the effects may be independent of cholesterol-lowering activity.

Induction of hepatic apolipoprotein A-I gene expression by the isoflavones quercetin and isoquercetrin.

AIMS: Phytochemicals such as flavonoids, vitamins, and polyphenols have been shown to have beneficial effects in metabolic disease. To determine if select flavonoids regulate hepatic apolipoprotein A-I (apo A-I) and high-density lipoprotein (HDL) synthesis, we examined the effects of quercetin, isoquercetin, and myrescetin on apo A-I gene expression in HepG2 (hepatocytes) and Caco-2 (intestinal) cells. MAIN METHODS: Apo A-I gene expression was measured by Western blotting, quantitative reverse-transcription polymerase chain reaction, and transient transfection. Estrogen receptor α (ESR1) and estrogen receptor ß expression were measured by Western blotting, and ESR1 expression was inhibited using ESR1-specific short inhibitory RNA (siRNA). KEY FINDINGS: Quercetin and isoquercetin, but not myrecetin, induced apo A-I protein and mRNA synthesis, and induced apo A-I promoter activity. Induction by quercetin required an estrogen-responsive region of the apo A-I promoter. Addition of estrogen receptor blocker ICI-182780 to quercetin-treated cells inhibited the effects of quercetin on apo A-I gene expression. Down-regulation of ESR1 with ESR1 siRNA had no effect on basal apo A-I gene expression; however it prevented quercetin-mediated induction of apo A-I gene expression. SIGNIFICANCE: We conclude that quercetin induces apo A-I gene expression at least in part through induction of ESR1 and may be useful in treating hypoalphalipoproteinemia.