Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone

Abstract

Statins block de novo synthesis of cholesterol by inhibiting the enzyme, HMG CoA reductase. The product of this reaction, mevalonic acid, is also a precursor of isoprenoids, molecules required for the activation of signalling G-proteins, such as Ras. Signal transduction pathways involving Ras are important for cell survival and this may be why statins induce apoptotic death of several cell types. Given that statins are used to treat vascular disease, it is surprising that no studies have been conducted on vascular endothelial cells. For this reason, we have tested the effect of fluvastatin (FS) on the endothelial cell line EA.hy 926. Here we show that FS, at concentrations from 1 to 2 µM, blocks growth and induces apoptosis of the endothelial cell line, EA.hy 926. As considerable redundancy exists in cell signalling pathways for cell survival, toxicity of FS under more physiological conditions might be prevented by pathways that do not require Ras, such as those activated by adrenal or sex steroids. To test this hypothesis, first RT-PCR analysis was performed for nuclear receptor mRNA expression. This revealed the presence of mRNA for the androgen receptor (AR) and glucocorticoid receptor (GR). The effect of the AR agonist, dihydrotestosterone (DHT), and the GR agonist, dexamethasone (Dex), was then tested. Whilst DHT (100 nM) had no effect on FS-induced cell death, Dex (1 µM) blocked FS-induced apoptosis. Cell cycle analysis revealed that 24 h exposure to FS prevented cells from leaving G 1 and 24-48 h later a marked sub-G 1 peak was observed. Dex was able to reduce the sub-G 1 peak, but it failed to reduce accumulation of cells in G 1 . Further studies revealed that, in addition to blocking FS-induced apoptosis, Dex was able to block apoptosis of EA.hy 926 cells induced by serum deprivation, tumour necrosis factor-, oxidants, DNA damage and mitochondrial disruption. This study strongly suggests that glucocorticoids have a role to play in preventing vascular injury and they may provide a reason why statins are apparently not toxic to vascular endothelial cells in vivo.

Changes in mitotic reorientation and Wnt/AR signaling in rat prostate epithelial cells exposed to subchronic testosterone

“…Although numerous studies have investigated the association between Ran and prostate cancer (23), more recent studies have investigated Ran in the context of benign proliferation of prostate cells (24,25). In the present study, the upregulation of the Ran gene was confirmed using RT-PCR, and the results suggested that Ran upregulation may contribute to prostate cell proliferation in BPH.…”

Pharmacological actions of statins: potential utility in COPD

“…Given these diverse pathways and anatomically distant events, what evidence exists to suggest that statin therapy (or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) might affect any of these pathological events? Matrix remodelling MM Reduced lung parenchymal destruction and MMP 9 activity in smoke exposed rat lung [74,75] HM ex vivo (bronchial epithelial Increase apoptosis in human vascular endothelial cells [84,86] Oxidant response HM in vivo (PMN) Reduce IL-8 release from neutrophils and neutrophil derived reactive oxidant species [77] HM in vivo (serum), MM Strong anti-oxidant properties [87,88] Mucus production MM Reduced LPS-induced goblet cell hyperplasia in bronchial epithelium and Muc5A induced mucus hypersecretion community acquired pneumonia (table 2) [102][103][104][105][106][107][108][109]. However, unlike the studies in COPD, the results in pneumonia are not consistent.…”

“…Studies have shown that statins reduce neutrophil influx in the lung which might have a strong effect on attenuating the downstream inflammatory events, such as macrophage influx, lymphocyte activation and inhibition of cytokine release, in particular IL-8 that appears central to the neutrophil inflammation of the lung [67][68][69][70][71][72][73][74][75][76][77][80][81][82][83][84][85][86][87][88]. The inhibition of IL-6, IL-8 and GM-CSF expression by statins has been shown in cell cultures of human BEC [65,70].…”

“…Statins also have effects on IL-6 levels in the systemic circulation and the effects of anti-oxidants on muscle atrophy [70, 73-77, 80, 87, 88]. Statins also inhibit apoptosis, which has been linked to both COPD and lung cancer [83][84][85][86]116]. The many pathways affected by statins are shown in figures 1 and 2, where the site of an inhibitory effect of statins based on animal or human studies are clearly shown (table 1).…”

Simvastatin as a Modulator of Tissue Remodeling through Inhibition of Matrix Metalloproteinase (MMP) Release from Human Lung Fibroblasts

“…Taken together, statins attenuate production of pro-inflammatory cytokines, inhibit MMP activation and induce apoptosis in variety types of cells 5 . We hypothesized that simvastatin can regulating human lung fibroblast function in wound repair and tissue remodeling following inflammatory lung injury through inhibiting MMP release from the fibroblast in collagen gel.…”