Premium
Simvastatin induces a central hypotensive effect via Ras‐mediated signalling to cause eNOS up‐regulation
Author(s) -
Cheng WenHan,
Ho WenYu,
Chang ChienFeng,
Lu PeiJung,
Cheng PeiWen,
Yeh TungChen,
Hong LingZong,
Sun GwoChing,
Hsiao Michael,
Tseng ChingJiunn
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12317
Subject(s) - simvastatin , enos , mapk/erk pathway , ly294002 , statin , pharmacology , endocrinology , protein kinase a , kinase , medicine , pi3k/akt/mtor pathway , signal transduction , chemistry , nitric oxide , nitric oxide synthase , biochemistry
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 ( LY 294002) or a MAPK ‐ ERK kinase ( MEK ) inhibitor ( PD 98059). 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 ERK 1/2, ribosomal protein S6 kinase ( RSK ), A kt and decreased eNOS phosphorylation. Likewise, administration of A kt and ERK 1/2 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.