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: Srinivas Sriramula, Huijing Xia, Ping Xu, Eric Lazartigues
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 65 Issue 3 Pg. 577-86 (Mar 2015) ISSN: 1524-4563 [Electronic] United States
• PMID: 25489058 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• Antioxidants
• Isoenzymes
• Membrane Proteins
• Desoxycorticosterone Acetate
• Nitric Oxide Synthase
• Ptgs2 protein, mouse
• Cyclooxygenase 1
• Cyclooxygenase 2
• Ptgs1 protein, mouse
• Proto-Oncogene Proteins c-akt
• Peptidyl-Dipeptidase A
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2

Topics

• Angiotensin-Converting Enzyme 2
• Animals
• Antioxidants (metabolism)
• Brain (metabolism)
• Cyclooxygenase 1 (genetics, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Desoxycorticosterone Acetate (adverse effects)
• Disease Models, Animal
• Encephalitis (metabolism, prevention & control)
• Gene Silencing
• Hypertension (chemically induced, metabolism, prevention & control)
• Isoenzymes (metabolism)
• MAP Kinase Signaling System (physiology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Transgenic
• Nitric Oxide Synthase (metabolism)
• Oxidative Stress (physiology)
• Peptidyl-Dipeptidase A (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Up-Regulation