Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

Wu, Kay L H; Chao, Yung-Mei; Tsay, Shiow-Jen; Chen, Chen Hsiu; Chan, Samuel H.H.; Dovinová, Ima; Chan, Julie Y.H.

doi:10.1161/hypertensionaha.114.03777

Cited by 37 publications

(42 citation statements)

References 59 publications

(59 reference statements)

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“…44 The latter two studies focused on other effects of PPAR-γ activity and did not measure the indicators of RAS activity and inflammation reported here.…”

Section: Discussionmentioning

confidence: 99%

Activation of Central PPAR-γ Attenuates Angiotensin II–Induced Hypertension

Xue

Wei

et al. 2015

Hypertension

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Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension.

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“…44 The latter two studies focused on other effects of PPAR-γ activity and did not measure the indicators of RAS activity and inflammation reported here.…”

Section: Discussionmentioning

confidence: 99%

Activation of Central PPAR-γ Attenuates Angiotensin II–Induced Hypertension

Xue

Wei

et al. 2015

Hypertension

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“…Therapeutic targeting of uncoupled eNOS was recently reviewed in detail (Risbano and Gladwin, ) (see also this virtual BJP issue Daiber et al .). Of note, also other NOS isoforms may uncouple and produce superoxide instead of • NO as shown for nNOS in models of metabolic syndrome and angiotensin‐II induced hypertension (Zhang et al , ; Wu et al , ). Moreover, a protective role of nNOS in preventing eNOS uncoupling was reported (Idigo et al , ).…”

Section: Redox Regulation Of Vascular Function By Oxidative Degradatimentioning

confidence: 99%

Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function

Daiber

Lisa

Oelze

et al. 2016

British J Pharmacology

224

202

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Cardiovascular diseases are associated with and/or caused by oxidative stress. This concept has been proven by using the approach of genetic deletion of reactive species producing (pro-oxidant) enzymes as well as by the overexpression of reactive species detoxifying (antioxidant) enzymes leading to a marked reduction of reactive oxygen and nitrogen species (RONS) and in parallel to an amelioration of the severity of diseases. Likewise, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of antioxidant RONS detoxifying enzymes. Thus, the consequences of the interaction (redox crosstalk) of superoxide/hydrogen peroxide produced by mitochondria with other ROS producing enzymes such as NADPH oxidases (Nox) are of outstanding importance and will be discussed including the consequences for endothelial nitric oxide synthase (eNOS) uncoupling as well as the redox regulation of the vascular function/tone in general (soluble guanylyl cyclase, endothelin-1, prostanoid synthesis). Pathways and potential mechanisms leading to this crosstalk will be analysed in detail and highlighted by selected examples from the current literature including hypoxia, angiotensin II-induced hypertension, nitrate tolerance, aging and others. The general concept of redox-based activation of RONS sources via "kindling radicals" and enzyme-specific "redox switches" will be discussed providing evidence that mitochondria represent key players and amplifiers of the burden of oxidative stress. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations ΔΨ m , mitochondrial membrane potential; 5-HD, 5-hydroxydecanoic acid; ADMA, asymmetric dimethylarginine; AT-II, angiotensin-II; BH 4 , tetrahydrobiopterin; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; GCH-1, GTP cyclohydrolase-1; K ATP ,, ATP-sensitive potassium channel; MAO, monoamine oxidase (isoforms A and B); MAPK, mitogen-activated protein kinases; MitoSOX, triphenylphosphonium dihydroethidium (mitochondria-targeted superoxide probe); MitoQ, triphenylphosphonium quinone (mitochondria-targeted antioxidant); MnSOD, manganese superoxide dismutase; mPTP, mitochondrial permeability transition pore; mtK ATP ,, mitochondrial K ATP ; mtROS, mitochondrial reactive oxygen species; nNOS, neuronal nitric oxide synthase; Nox, NADPH oxidase catalytic subunit (isoforms 1, 2 and 4); PGIS, prostacyclin; PKC, protein kinase C; RNS, reactive nitrogen species (accounts in the present review mostly for peroxynitrite and nitrogen dioxide); ROS, reactive oxygen species (accounts in the present review mostly for superoxide and hydrogen peroxide); sGC, soluble guanylyl cyclase; SOD, superoxide dismutase; Src (or cSrc), tyrosine kinase; XDH, xanthine dehydrogenase; XO, xanthine oxidase...

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“…exacerbated RVLM neuronal oxidative stress and the elevated BP in hypertension (Wu et al, 2014). Second, compared with normotensive controls, activation of RVLM NMDAR causes greater elevation in BP in spontaneously hypertensive rats (Lin et al, 1995).…”

Section: Discussionmentioning

confidence: 97%

Central GPR109A Activation Mediates Glutamate-Dependent Pressor Response in Conscious Rats

Rezq

Abdel‐Rahman

2015

Journal of Pharmacology and Experimental Therapeutics

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G protein-coupled receptor 109A (GPR109A) activation by its ligand nicotinic acid (NA) in immune cells increases Ca 21 levels, and Ca 21 induces glutamate release and oxidative stress in central blood pressure (BP)-regulating nuclei, for example, the rostral ventrolateral medulla (RVLM), leading to sympathoexcitation. Despite NA's ability to reach the brain, the expression and function of its receptor GPR109A in the RVLM remain unknown. We hypothesized that NA activation of RVLM GPR109A causes Ca 21-dependent L-glutamate release and subsequently increases neuronal oxidative stress, sympathetic activity, and BP. To test this hypothesis, we adopted a multilevel approach, which included pharmacologic in vivo studies along with ex vivo and in vitro molecular studies in rat pheochromocytoma cell line (PC12) cells (which exhibit neuronal phenotype). We present the first evidence for GPR109A expression in the RVLM and in PC12 cells. Next, we showed that RVLM GPR109A activation (NA) caused pressor and bradycardic responses in conscious rats. The resemblance of these responses to those caused by intra-RVLM glutamate and their attenuation by NMDA receptor (NMDAR) blockade (2-amino-5-phosphonopentanoic acid) and enhancement by L-glutamate uptake inhibition (L-trans-pyrrolidine-2,4-dicarboxylic acid, PDC) supported our hypothesis. NA increased Ca 21 , glutamate, nitric oxide and reactive oxygen species (ROS) levels in PC12 cells and increased RVLM ROS levels. The inactive NA analog isonicotinic acid failed to replicate the cardiovascular and biochemical effects of NA. Further, GPR109A knockdown (siRNA) abrogated the biochemical effects of NA in PC12 cells. These novel findings yield new insight into the role of RVLM GPR109A in central BP control.

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Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

Cited by 37 publications

References 59 publications

Activation of Central PPAR-γ Attenuates Angiotensin II–Induced Hypertension

Activation of Central PPAR-γ Attenuates Angiotensin II–Induced Hypertension

Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function

Central GPR109A Activation Mediates Glutamate-Dependent Pressor Response in Conscious Rats

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