Brain-Targeted Angiotensin-Converting Enzyme 2 Overexpression Attenuates Neurogenic Hypertension by Inhibiting Cyclooxygenase-Mediated Inflammation
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.
- angiotensin-converting enzyme 2
- paraventricular nucleus
- renin-angiotensin system
- Received October 2, 2014.
- Revision received October 18, 2014.
- Accepted November 19, 2014.
- © 2014 American Heart Association, Inc.