Role of nitric oxide synthase uncoupling at rostral ventrolateral medulla in redox-sensitive hypertension associated with metabolic syndrome.
Metabolic syndrome (MetS), which is rapidly becoming prevalent worldwide, is long known to be associated with hypertension and recently with oxidative stress. Of note is that oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, contributes to sympathoexcitation and hypertension. This study sought to identify the source of tissue oxidative stress in RVLM and their roles in neural mechanism of hypertension associated with MetS. Adult normotensive rats subjected to a high-fructose diet for 8 weeks developed metabolic traits of MetS, alongside increases in sympathetic vasomotor activity and blood pressure. In RVLM of these MetS rats, the tissue level of reactive oxygen species was increased, nitric oxide (NO) was decreased, and mitochondrial electron transport capacity was reduced. Whereas the protein expression of neuronal NO synthase (nNOS) or protein inhibitor of nNOS was increased, the ratio of nNOS dimer/monomer was significantly decreased. Oral intake of pioglitazone or intracisternal infusion of tempol or coenzyme Q10 significantly abrogated all those molecular events in high-fructose diet-fed rats and ameliorated sympathoexcitation and hypertension. Gene silencing of protein inhibitor of nNOS mRNA in RVLM using lentivirus carrying small hairpin RNA inhibited protein inhibitor of nNOS expression, increased the ratio of nNOS dimer/monomer, restored NO content, and alleviated oxidative stress in RVLM of high-fructose diet-fed rats, alongside significantly reduced sympathoexcitation and hypertension. These results suggest that redox-sensitive and protein inhibitor of nNOS-mediated nNOS uncoupling is engaged in a vicious cycle that sustains the production of reactive oxygen species in RVLM, resulting in sympathoexcitation and hypertension associated with MetS.
['Wu|Kay L H|KL|', 'Chao|Yung-Mei|YM|', 'Tsay|Shiow-Jen|SJ|', 'Chen|Chen Hsiu|CH|', 'Chan|Samuel H H|SH|', 'Dovinova|Ima|I|', 'Chan|Julie Y H|JY|']
D000818:Animals D001794:Blood Pressure D015153:Blotting, Western D056445:Cytoplasmic Dyneins D059305:Diet, High-Fat D006973:Hypertension D007004:Hypoglycemic Agents D008297:Male D008526:Medulla Oblongata D024821:Metabolic Syndrome D018613:Microscopy, Confocal D019255:NADPH Oxidases D052248:Nitric Oxide Synthase Type I D010084:Oxidation-Reduction D000077205:Pioglitazone D034622:RNA Interference D051381:Rats D017207:Rats, Sprague-Dawley D017382:Reactive Oxygen Species D013482:Superoxide Dismutase D045162:Thiazolidinediones D014666:Vasomotor System
nitric oxide hypertension reactive oxygen species metabolic cardiovascular syndrome sympathetic nervous system