Wen-Han Cheng and Wen-Yu Ho contributed equally to this work.
Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation
Article first published online: 1 OCT 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 170, Issue 4, pages 847–858, October 2013
How to Cite
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. and Tseng, C.-J. (2013), Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation. British Journal of Pharmacology, 170: 847–858. doi: 10.1111/bph.12317
- Issue published online: 1 OCT 2013
- Article first published online: 1 OCT 2013
- Accepted manuscript online: 25 JUL 2013 05:38AM EST
- Manuscript Accepted: 21 JUL 2013
- Manuscript Revised: 8 JUL 2013
- Manuscript Received: 8 FEB 2013
- National Science Council. Grant Numbers: NSC100-2321-B-075B-002, NSC 101-2320-B-075B-002-MY3
- Kaohsiung Veterans General Hospital. Grant Number: VGHKS101-024
- Kaohsiung Medical University Hospital, Kaohsiung Medical University
- nucleus tractus solitarii;
- nitric oxide;
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).
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).
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.