title: Role of nitric oxide synthase uncoupling at rostral ventrolateral medulla in redox-sensitive hypertension associated with metabolic syndrome.
abstract: 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.
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.).
authors: Kay L H
authors: KL
authors: Wu
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.).
authors: Yung-Mei
authors: YM
authors: Chao
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.).
authors: Shiow-Jen
authors: SJ
authors: Tsay
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.).
authors: Chen Hsiu
authors: CH
authors: Chen
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.).
authors: Samuel H H
authors: SH
authors: Chan
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.). jchan@adm.cgmh.org.tw Ima.Dovinova@savba.sk.
authors: Ima
authors: I
authors: Dovinova
authors: From the Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (K.L.H.W., Y.M.C., S.H.H.C., J.Y.H.C.); Institute of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan (S.J.T.); Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (C.H.C.); and Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia (I.D.). jchan@adm.cgmh.org.tw Ima.Dovinova@savba.sk.
authors: Julie Y H
authors: JY
authors: Chan
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism*; D018613:Microscopy, Confocal; D019255:NADPH Oxidases / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010084:Oxidation-Reduction; D000077205:Pioglitazone; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D052248:Nitric Oxide Synthase Type I; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C486069:Dynll1 protein, rat; D056445:Cytoplasmic Dyneins; D000077205:Pioglitazone
keywords: hypertension; metabolic cardiovascular syndrome; nitric oxide; reactive oxygen species; sympathetic nervous system