Abstract 220: High Sodium Diet Increases Gut Th17 Differentiation and Induces Neurovascular and Cognitive Dysfunction Through Il-17
High sodium diet (HSD) is a risk factor for stroke and dementia, independent of its effect on blood pressure (BP), but the mechanisms remain unclear. To investigate the cerebrovascular and cognitive impact of HSD, we fed HSD (4-8% NaCl) or normal diet (ND; 0.5% NaCl) to C57BL/6 mice for 12 weeks and assessed cerebral blood flow (CBF) in the somatosensory cortex by laser-Doppler flowmetry. HSD did not increase BP, but attenuated the CBF increase induced by neocortical application of acetylcholine (ACh)(-30.6±0.5%; p<0.05; n=8), a response mediated by endothelial nitric oxide synthase (eNOS), without affecting the response to the smooth muscle relaxant adenosine. These vascular changes were associated with a deficit in novel object exploration (-24±5%; p<0.05; n=15) and spatial learning (Barnes maze) (-31±20%; p<0.05; n=10), suggesting cognitive impairment. The ACh response suppression was associated with increased inhibitory eNOS phosphorylation in pial microvessels (≈1.6 fold increase vs ND; p<0.05; n=7). Since HSD promotes expansion of intestinal helper T lymphocytes producing the vasotoxic cytokine IL17 (Th17) (Nature, 496:518, 2013), we investigated whether IL-17 contributes to the effects of HSD. HSD increased intestinal Th17 cells (+69±20%; p<0,05; n=8), as well as IL-17 plasma levels (ND 0.9±0.2pg/ml; HSD 6.5±1.4pg/ml; p<0.05; n=5). Furthermore, genetic deletion of IL-17 or systemic administration of IL-17 blocking antibodies counteracted the vascular and cognitive effects of HSD, whereas injection of IL-17 (1μg;q.d.x7days;i.p.) reproduced them in full. In brain endothelial cell cultures, IL-17 (10ng/ml) suppressed ACh-induced NO production (-31±2%; p<0,05; n=3), by increasing Rho-kinase-dependent inhibitory eNOS phosphorylation. We conclude that HSD induces profound alterations in neurovascular regulation and cognitive function. The effect is mediated by expansion of intestinal Th17 cells and increased circulating IL-17, which, in turn, leads to inhibitory eNOS phosphorylation and reduced NO production through Rho kinase. The data suggest a neurovascular mechanism for the increased risk of stroke and dementia with HSD, and identifies IL17 as a putative therapeutic target for the deleterious effects of high salt on the brain.
- Cerebrovascular circulation
- Endothelial function
- Nitric oxide synthase
- Vascular cognitive impairment
Author Disclosures: G. Faraco: None. D. Brea: None. G. Wang: None. L. Garcia Bonilla: None. G. Racchumi: None. H. Chang: None. I. Buendia: None. K. Koizumi: None. J. Anrather: None. C. Iadecola: None.
This research has received full or partial funding support from the American Heart Association, Founders - Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont.
- © 2017 by American Heart Association, Inc.