The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are unequivocally useful for lowering cholesterol levels in patients with dyslipidemias. In addition to cholesterol lowering properties, statins exert a number of pleiotropic, vascular-protective effects include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties. Since endothelial dysfunction and reactive oxygen species (ROS) are important pathophysiological determinants of essential hypertension, these actions of statins raise the possibility that statin therapy may be useful for simultaneously clinical hypertension management. However, the signaling mechanisms of statins that improve hypertension remain unclear. Our previous study showed, in the NTS, insulin may decrease blood pressure and heart rates through PI3K-Akt-eNOS pathway, and NTS integrates convergent information from peripheral baroreceptors and central cardiovascular regulatory center. Statins also prevent the synthesis of other important isoprenoid intermediates of the cholesterol biosynthetic pathway, members of the Ras and Rac1 GTPase family are major substrates for posttranslational modification by isoprenylation and may be important targets for inhibition by statins. Statins could inhibit Rac1 isoprenylation and Rac1-mediated nicotinamide adenine dinucleotide phosphate oxidase activity attenuates reactive oxygen species production. The aim of this study was to investigate the possible signaling pathways involved in simvastatin-mediated blood pressure regulation in the nucleus tractus solitarii (NTS). Male 20-week-old spontaneously hypertensive rats (SHR) were divided into two groups: control group and intracerebroventricular injection with simvastatin group for three days. We found that systolic blood pressure measured with tail-cuff method of the simvastatin-treated rats decreased significantly, and the NO level in the NTS was significantly increased. In addition, we observed that simvastatin could lower the ROS level and increase Ras GTPase activity in the NTS. Immunoblotting and immunohistochemistry analysis further showed that simvastatin increased the phosphorylation ratio of ERK1/2, Akt, and endothelial nitric oxide synthase (eNOS) in the NTS. Taken together, these results suggest that eNOS signaling in the NTS may play an important role in simvastatin-induced blood pressure lowering effects.
Keywords: statins, nucleus tractus solitarii, nitric oxide, oxidative stress, central cardiovascular regulatory, isoprenylation
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0727111-110359 |
| Date | 27 July 2011 |
| Creators | Chang, Chien-Feng |
| Contributors | Michael Hsiao, Yow-Ling Shiue, Long-Sen Chang, Pei-Jung Lu, Ching-Jiunn Tseng |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0727111-110359 |
| Rights | not_available, Copyright information available at source archive |
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