Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation

Wen Han Cheng, Wen Yu Ho, Chien Feng Chang, Pei Jung Lu, Pei Wen Cheng, Tung Chen Yeh, Ling Zong Hong, Gwo Ching Sun, Michael Hsiao, Ching Jiunn Tseng

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Abstract

Background and Purpose Clinical studies indicate that statins have a BP-lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up-regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin-mediated BP regulation in the nucleus tractus solitarii (NTS). Experimental Approach To investigate the involvement of Ras and other signalling pathways in simvastatin-induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras-specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI-2133), a PI3K inhibitor (LY294002) or a MAPK-ERK kinase (MEK) inhibitor (PD98059). Key Results FTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin-induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS-positive cells in the NTS. Conclusions and Implications Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras-mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways, which then up-regulates eNOS activation.

Original languageEnglish
Pages (from-to)847-858
Number of pages12
JournalBritish Journal of Pharmacology
Volume170
Issue number4
DOIs
Publication statusPublished - 2013 Oct 1

All Science Journal Classification (ASJC) codes

  • Pharmacology

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    Cheng, W. H., Ho, W. Y., Chang, C. F., Lu, P. J., Cheng, P. W., Yeh, T. C., Hong, L. Z., Sun, G. C., Hsiao, M., & Tseng, C. J. (2013). Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation. British Journal of Pharmacology, 170(4), 847-858. https://doi.org/10.1111/bph.12317