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

被引:23
作者
Cheng, Wen-Han [1 ,2 ]
Ho, Wen-Yu [3 ,4 ]
Chang, Chien-Feng [5 ]
Lu, Pei-Jung [6 ]
Cheng, Pei-Wen [1 ]
Yeh, Tung-Chen [7 ]
Hong, Ling-Zong [8 ]
Sun, Gwo-Ching [9 ]
Hsiao, Michael [10 ]
Tseng, Ching-Jiunn [1 ,2 ,5 ,11 ]
机构
[1] Kaohsiung Vet Gen Hosp, Dept Med Educ & Res, Kaohsiung 813, Taiwan
[2] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan
[3] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Internal Med, Div Gen Internal Med, Kaohsiung, Taiwan
[4] Kaohsiung Med Univ, Coll Med, Fac Med, Dept Internal Med, Kaohsiung, Taiwan
[5] Natl Sun Yat Sen Univ, Inst Biomed Sci, Kaohsiung 80424, Taiwan
[6] Natl Cheng Kung Univ, Inst Clin Med, Tainan 70101, Taiwan
[7] Kaohsiung Vet Gen Hosp, Dept Internal Med, Div Cardiol, Kaohsiung, Taiwan
[8] Taichung Vet Gen Hosp, Dept Med Educ & Res, Taichung, Taiwan
[9] Yuli Vet Hosp, Dept Anesthesiol, Hualien, Taiwan
[10] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan
[11] Natl Def Med Ctr, Dept Pharmacol, Taipei, Taiwan
关键词
statins; nucleus tractus solitarii; nitric oxide; Ras; hypertension; isoprenylation; NITRIC-OXIDE SYNTHASE; ROSTRAL VENTROLATERAL MEDULLA; NUCLEUS-TRACTUS-SOLITARII; LIPID-LOWERING THERAPY; BLOOD-PRESSURE; CARDIOVASCULAR FUNCTIONS; ENDOTHELIAL-CELLS; NEURAL MECHANISMS; BRAIN-STEM; IN-VITRO;
D O I
10.1111/bph.12317
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background and PurposeClinical 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 ApproachTo 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 ResultsFTS 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 ImplicationsSimvastatin 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.
引用
收藏
页码:847 / 858
页数:12
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