Abstract
BackgroundSalvianolic acid B (Sal B) is one of the most bioactive components of Salvia miltiorrhiza, a traditional Chinese herbal medicine that has been commonly used for prevention and treatment of cerebrovascular disorders. However, the mechanism responsible for such protective effects remains largely unknown. It has been considered that cerebral endothelium apoptosis caused by reactive oxygen species including hydrogen peroxide (H2O2) is implicated in the pathogenesis of cerebrovascular disorders.Methodology and Principal FindingsBy examining the effect of Sal B on H2O2-induced apoptosis in rat cerebral microvascular endothelial cells (rCMECs), we found that Sal B pretreatment significantly attenuated H2O2-induced apoptosis in rCMECs. We next examined the signaling cascade(s) involved in Sal B-mediated anti-apoptotic effects. We showed that H2O2 induces rCMECs apoptosis mainly through the PI3K/ERK pathway, since a PI3K inhibitor (LY294002) blocked ERK activation caused by H2O2 and a specific inhibitor of MEK (U0126) protected cells from apoptosis. On the other hand, blockage of the PI3K/Akt pathway abrogated the protective effect conferred by Sal B and potentated H2O2-induced apoptosis, suggesting that Sal B prevents H2O2-induced apoptosis predominantly through the PI3K/Akt (upstream of ERK) pathway.SignificanceOur findings provide the first evidence that H2O2 induces rCMECs apoptosis via the PI3K/MEK/ERK pathway and that Sal B protects rCMECs against H2O2-induced apoptosis through the PI3K/Akt/Raf/MEK/ERK pathway.
Highlights
Apoptosis is a process of programmed cell death in which defective and harmful cells are eliminated from a multicellular organism so as to maintain its homeostasis
The results showed that amounts of phosphorylated extracellular signal-regulated kinase (ERK) in H2O2-stimulated cells peaked at 30 min, that they returned to near basal concentrations after 3 h, but that pretreatment with Salvianolic acid B (Sal B) resulted in a marked inhibition of these cellular responses, and that incubation of rat cerebral microvascular endothelial cells (rCMECs) with Sal B alone significantly reduced basal ERK phosphorylation (Fig. 2B)
This study yielded four major findings: (1) Exposure rCMECs to H2O2 caused dose-dependent apoptosis, which could be prevented by pretreatment with Sal B. (2) Activation of the MEK/ERK pathway acted as a pro-apoptotic signal in H2O2-treated rCMECs; this activation was in turn dependent on PI3K activation
Summary
Apoptosis is a process of programmed cell death in which defective and harmful cells are eliminated from a multicellular organism so as to maintain its homeostasis. Cerebral microvascular endothelial cells (CMECs) and intercellular tight junctions constitute the basic structure of the blood-brain barrier (BBB) which is responsible for regulating the trafficking of cells, substrates, and other molecules into the brain [2]. By examining the effect of Sal B on H2O2-induced apoptosis in rat cerebral microvascular endothelial cells (rCMECs), we found that Sal B pretreatment significantly attenuated H2O2induced apoptosis in rCMECs. We examined the signaling cascade(s) involved in Sal B-mediated anti-apoptotic effects. We showed that H2O2 induces rCMECs apoptosis mainly through the PI3K/ERK pathway, since a PI3K inhibitor (LY294002) blocked ERK activation caused by H2O2 and a specific inhibitor of MEK (U0126) protected cells from apoptosis. Our findings provide the first evidence that H2O2 induces rCMECs apoptosis via the PI3K/MEK/ERK pathway and that Sal B protects rCMECs against H2O2-induced apoptosis through the PI3K/Akt/Raf/MEK/ERK pathway
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