High Mobility Group Box 1 Neutralization in the Brain Prevents Inflammation, Sympathoexcitation and Hypertension

Abstract

High mobility group box 1 (HMGB1) is a nuclear protein, that once translocated to cytoplasm, can act as a chemoattractant and a proinflammatory mediator. Post‐translationally modified HMGB1 can interact with different receptors, such as toll‐like receptor 4 (TLR4) and chemokine receptor CXC receptor 4 (CXCR4), to induce acute and chronic inflammation. We have previously showed that central TLR4 blockade delayed progression of hypertension and improved cardiac function. However, the involvement of HMGB1 and its interaction with TLR4 in the pathogenesis of hypertension has not been fully explored. Therefore, in this study, we investigated the role of HMGB1 in mediating hypertension, inflammation and sympathoexcitation. We hypothesized that blockade of HMGB1 prevents the development of hypertension. Chronic angiotensin II (AngII) infusion (200 ng/kg/min, SC, 14 days) significantly increased mean arterial pressure (telemetry) in male Sprague‐Dawley rats compared to saline‐infused controls (163 ±5 vs. 105 ±4 mmHg, n=7, p<0.01). AngII‐infusion significantly increased HMGB1 levels in the plasma (21 ±3 vs.15 ±2 ng/ml, p<0.01) and cerebrospinal fluid (34±3 vs. 21±1 ng/ml, p<0.01), and elevated HMGB1 protein expression (2.5 fold, n=6, p<0.01 vs. Control) in the brain hypothalamic paraventricular nucleus (PVN). Intracerebroventricular infusion of neutralizing monoclonal anti‐HMGB1 antibody (10 μg/kg/day) attenuated AngII‐induced hypertension (120 ±2 mmHg, p<0.01 vs. AngII). Furthermore, AngII‐infusion significantly increased expression of TNF, IL‐1, IL‐6, TLR4, CXCR4, and NF‐kB in the PVN, which was prevented by HMGB1 neutralization. AngII infusion resulted in sympathoexcitation, as indicated by increased plasma norepinephrine levels (1602 ±53 vs. 549 ±25 pg/ml, P<0.01 vs. Control), but this increase was blunted by HMGB1 neutralization (720 ±25 pg/ml, P<0.05 vs. AngII). Taken together, these data suggest that neutralization of HMGB1 in the brain reduces inflammation and decreases sympathoexcitation, thereby preventing the development of AngII‐induced hypertension.Support or Funding InformationThe American Heart Association, 15SDG25720021 (SS), 16GRNT30510012 (JF)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.