title: Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation.
abstract: Overactivity of the renin-angiotensin system, oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that angiotensin-converting enzyme 2 (ACE2) overexpression in the brain attenuates the development of deoxycorticosterone acetate-salt hypertension, a neurogenic hypertension model with enhanced brain renin-angiotensin system and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen-activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. Deoxycorticosterone acetate-salt hypertension significantly increased expression of Nox-2 (+61±5%), Nox-4 (+50±13%), and nitrotyrosine (+89±32%) and reduced activity of the antioxidant enzymes, catalase (-29±4%) and superoxide dismutase (-31±7%), indicating increased oxidative stress in the brain of nontransgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. Deoxycorticosterone acetate-salt-induced reduction of neuronal nitric oxide synthase expression (-26±7%) and phosphorylated endothelial nitric oxide synthase/total endothelial nitric oxide synthase (-30±3%), and enhanced phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2 in the paraventricular nucleus, were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the paraventricular nucleus. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuroinflammation, ultimately attenuating Deoxycorticosterone acetate-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuroinflammation, improves antioxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Neurosciences and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sriramula
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Neurosciences and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans.
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Neurosciences and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Neurosciences and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans. elazar@lsuhsc.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D064791:Desoxycorticosterone Acetate / Q000009:adverse effects; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism / Q000517:prevention & control*; D020868:Gene Silencing; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D007527:Isoenzymes; D008565:Membrane Proteins; D064791:Desoxycorticosterone Acetate; D019001:Nitric Oxide Synthase; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: angiotensin-converting enzyme 2; cyclooxygenases; hypertension; paraventricular nucleus; renin-angiotensin system