Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) ...into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2(-/y)) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2(-/y). Post infusion, plasma and brain AngII levels were also significantly higher in ACE2(-/y), although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2(-/y) mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2(-/y) mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2(-/y) mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.
ACE2 plays a protective role in the central regulation of autonomic function by reducing oxidative stress. To assess the mechanisms involved, ACE2 KO and non transgenic (NT) mice (n=6) were infused ...with AngII (osmotic pump: 600 ng/kg/min sc) and infected with a hACE2 or control (eGFP) adenovirus (2×106 pfu, 200 nL) in the PVN 3d post infusion. After 10d of infusion, NADPH oxidase (NOX) and superoxide dismutase (SOD) activity (U/mg), and SOD 1 and 2 protein expression (Immunofluorescence, arbitrary units) were assessed in the brainstem. NOX (2.8 ±0.1 vs. 1.0 ±0.02) and SOD activities (1.4 ±0.1 vs. 1.0 ±0.05; P<0.05) were significantly increased in KO mice (P<0.05 vs. NT), as well as SOD1 (2.5 ±0.6 vs. 1.0 ±0.04) and SOD2 (1.7 ±0.1 vs. 1.0 ±0.05) expression (P<0.05 vs. NT). Post AngII, NOX activity was increased in both KO (3.1 ±0.2) and NT (2.1 ±0.2) and remained higher in the KO (P<0.05 vs. NT), while SOD1 and 2 expression and activity were only increased in the NT (2.3±0.6; 1.6±0.1; 1.2±0.1; respectively, P<0.05 vs. baseline). ACE2 over‐expression reduced NOX activity in the KO without changing SOD expression or activity. These data suggest that ACE2 gene deletion promotes AngII‐mediated oxidative stress, and ACE2 compensation in the PVN decreases oxidative stress in the brainstem by inhibiting NOX activation, thus contributing to the improvement of autonomic function in this model. (HL093178 and APS Postdoctoral Fellowship)
Organic aerosols in the atmosphere are composed of a wide variety of species, reflecting the multitude of sources and growth processes of these particles. Especially challenging is predicting how ...these particles act as cloud condensation nuclei (CCN). Previous studies have characterized the CCN efficiency for organic compounds in terms of a hygroscopicity parameter, κ. Here we extend these studies by systematically testing the influence of the number and location of molecular functional groups on the hygroscopicity of organic aerosols. Organic compounds synthesized via gas-phase and liquid-phase reactions were characterized by high-performance liquid chromatography coupled with scanning flow CCN analysis and thermal desorption particle beam mass spectrometry. These experiments quantified changes in κ with the addition of one or more functional groups to otherwise similar molecules. The increase in κ per group decreased in the following order: hydroxyl ≫ carboxyl > hydroperoxide > nitrate ≫ methylene (where nitrate and methylene produced negative effects, and hydroperoxide and nitrate groups produced the smallest absolute effects). Our results contribute to a mechanistic understanding of chemical aging and will help guide input and parametrization choices in models relying on simplified treatments such as the atomic oxygen:carbon ratio to predict the evolution of organic aerosol hygroscopicity.
Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I ...receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults using tamoxifen-regulated Cre deletion of IGF-IR in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 (Iba 1) microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.
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