Endothelial dysfunction in various vascular diseases is associated with reduced nitric oxide(NO) bioavailability.It has been clearly demonstrated that endothelial nitric oxide synthase(eNOS) uncoupling plays a key role in above vascular pathological status.eNOS uncoupling is characterized by eNOS generating super oxide rather than NO which may resulted from the increased oxidative stress,lack of eNOS protein cofactor tetrahydrobiopterin(BH4),or supplement shortage of eNOS substrate L-arginine.Accumulating evidences suggest that reversal of eNOS uncoupling by ether reduction of oxidative stress or promotion the bioavailability of BH4 and L-arginine may serve as a novel therapeutic strategy for endothelial dysfunction and cardiovascular diseases,such as hypertension,diabetes,and atherosclerosis.

Objective To evaluate the inflammatory response and the expressions of peroxisome proliferator-activated receptor(PPAR)isoforms(PPARα,PPARβ/δ,and PPARγ)in the brain(cortex,striatum,cerebellum)of spontaneously hypertensive rats(SHR).Methods Brain tissues(cortex,striatum,and cerebellum)were dissected from SHR and age-matched control Wistar-Kyoto rats.Myeloperoxidase(MPO)activity was measured in brain tissues as an index of neutrophil accumulation and the carbonyl protein content was analyzed by spectrophotometry to evaluate the protein oxidation.RT-PCR and Western blotting were performed to examine the expressions of inflammatory mediators(IL-1β,TNFα,ICAM-1,and iNOS)and nuclear factor PPARs(PPARα,PPARβ/δ,and PPARγ),respectively.Results(1)Systolic blood pressure of SHR was significantly higher than that of Wistar-Kyoto rats,(205.4±9.4)mm Hg versus(130.4±7.9)mm Hg(t=14.96,P＜0.01).(2)MPO activity of cortex,striatum,and cerebellum were markedly higher in SHR than in Wistar-Kyoto rats.Carbonyl protein levels of cortex,striatum,and cerebellum in Wistar-Kyoto rats and SHR were(3.27±0.43)nmol/mg versus(11.87±1.11)nmol/mg,(4.02±1.04)nmol/mg versus(14.06±1.36)nmol/mg,(5.94±0.71)nmol/mg versus(14.95±1.82)nmol/mg,indicating significantly higher levels of protein oxidation in SHR than Wistar-Kyoto rats(t=17.70,14.36,11.30,P＜0.05).Consistently,the expression of pro-inflammatory mediators(IL-1β,TNFα,ICAM-1,and iNOS)was upregulated when compared with Wistar-Kyoto rats.The difference between SHR and control Wistar-Kyoto rats was statistically significant except the mRNA expression of IL-1β in striatum,cerebellum and TNFα in cerebellum of SHR.All the above experimental data indicated the occurrence of inflammatory status in the brain tissue of hypertension.(3)mRNA and protein levels of brain PPAR isoforms(PPARα,PPARβ/δ,and PPARγ)of SHR increased significantly when compared with Wistar-Kyoto rats.Specifically.protein levels of PPARα in cortex.striatum,and cerebellum of SHR increased by 644.78%,791.95%,and 42.85%;PPARβ/δ increased by 106.72%,94.12%,and 161.44%;PPARγ was up-regulated by 2700.16%,790.81%,and 875.00%compared with that of Wistar-Kyoto rats,respectively.Conclusions The brain(cortex,striatum,and cerebellum)from SHR shows marked inflammatory status and increased expression of all PPAR isoforms.Increases in PPARs expression may play a compensatory role in the inflammatory response of the brain in SHR.