Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor family that act as transcription factors to regulate target gene expression. In addition to their well-known effects in regulation of glucose homeostasis and lipid metabolism, PPAR activators have recently been shown to exert antihypertensive effects, although the underlying mechanism is not clear. Our laboratory has previously demonstrated that oxidative stress of an augmented tissue level of superoxide anion (£R2¡E−) in the rostral ventrolateral medulla (RVLM), where promotor neurons for generation of sympathetic vasomotor outflow reside, contributes to neural mechanism of hypertension. I therefore propose to test in my thesis the hypothesis that protection against oxidative stress after activation of the PPARs in the RVLM may contribute to the antihypertensive effect of these transcription factors.
Experiments were performed in the spontaneously hypertensive rats (SHR) or normotensive Wistar-Kyoto (WKY) rats under anesthesia or conscious condition. Compared to WKY rats, microinjection bilaterally into the RVLM of a synthetic activator of PPAR£^, rosiglitazone (1 nmol), evoked significantly greater decreased in mean systemic arterial pressure (MSAP) and heart rate (HR) in SHR. These cardiovascular suppressive
effects of rosiglitazone were accompanied by greater decrease in tissue level of O2
- and upregulation of the antioxidant uncoupling proteins (UCPs) in the RVLM of SHR. Rosiglitazone also caused a significant greater increase in PPAR£^ expression in the nuclear extracts from RVLM of SHR than WKY rats. All these cellular events induced by rosiglitazone were antagonized by co-administration into the RVLM of the PPAR£^ inhibitor, GW9662 (5 nmol). This PPAR£^ inhibitor also significantly reversed the cardiovascular depressive effects of rosiglitazone. Together these results suggest that PPAR£^ in the RVLM may participate in central cardiovascular regulation by promoting hypotension and bradycardia via amelioration of O2- production and upregulation of antioxidant UCPs. Moreover, a downregulation of the PPAR£^ in the RVLM may contribute to neural mechanism of hypertension.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0730108-171605 |
| Date | 30 July 2008 |
| Creators | Wu, Chiung-ai |
| Contributors | Ming-Hong Tai, Alice Y.W. Chang, Samuel H.H. Chan, Julie Y.H. Chan |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | Cholon |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0730108-171605 |
| Rights | withheld, Copyright information available at source archive |
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