Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension

Abstract

BackgroundDespite the availability of several antihypertensive medications, the morbidity and mortality caused by hypertension is on the rise, suggesting the need for investigation of novel signaling pathways involved in its pathogenesis. Recent evidence suggests the role of toll-like receptor (TLR) 4 in various inflammatory diseases, including hypertension. The role of the brain in the initiation and progression of all forms of hypertension is well established, but the role of brain TLR4 in progression of hypertension has never been explored. Therefore, we investigated the role of TLR4 within the paraventricular nucleus (PVN; an important cardioregulatory center in the brain) in an animal model of human essential hypertension. We hypothesized that a TLR4 blockade within the PVN causes a reduction in mean arterial blood pressure (MAP), inflammatory cytokines and sympathetic drive in hypertensive animals.MethodsSpontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were administered either a specific TLR4 blocker, viral inhibitory peptide (VIPER), or control peptide in their PVN for 14 days. MAP was recorded continuously by radiotelemetry. PVN and blood were collected for the measurement of pro-inflammatory cytokines (Tumor Necrosis Factor (TNF)-α, interleukin (IL)-1β), anti-inflammatory cytokine IL-10, inducible nitric oxide synthase (iNOS), TLR4, nuclear factor (NF) κB activity and plasma norepinephrine (NE) and high mobility group box (HMGB)1 expression, respectively.ResultsHypertensive rats exhibited significantly higher levels of TLR4 in the PVN. TLR4 inhibition within the PVN attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, iNOS levels, and NFκB activity in SHR but not in WKY rats. These results were associated with a reduction in plasma NE and HMGB1 levels and an increase in IL-10 levels in SHR.ConclusionsThis study demonstrates that TLR4 upregulation in PVN plays an important role in hypertensive response. Our results provide mechanistic evidence that hypertensive response in SHR are mediated, at least in part, by TLR4 in the PVN and that inhibition of TLR4 within the PVN attenuates blood pressure and improves inflammation, possibly via reduction in sympathetic activity.

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

“…In the central nervous system, previous studies identified that HMGB1 inhibition attenuated microglia activation (15) and tissue inflammation in ischemia and reperfusion models (17,19,28). A recent study (14) from our group showed that SHR exhibited increased HMGB1 levels in the plasma and PVN and that TLR4 blockade in the PVN attenuated inflammation and hypertension. Another original observation of this study is that short-term aerobic training was able to normalize HMGB1 expression in the PVN, as well as in the cerebrospinal fluid and plasma.…”

“…Differently from the ANG II-induced hypertension model, which is mostly related to neurogenic drive, SHR exhibits both early autonomic dysfunction (34) and vascular remodeling (3,8). These findings explain the conflicting data: normalization of arterial pressure in ANG II-induced hypertension (7,13,18) and hypertension attenuation in the SHR after chronic blockade of hypothalamic inflammation (14). In previous studies, we also observed partial pressure fall in the SHR submitted to a similar training protocol, which was accompanied by normalization of wall/lumen ratio of skeletal muscle and myocardium arterioles, but only after 4 wk of aerobic exercise training (10,31,32).…”

“…Plasma and cerebrospinal fluid levels of HMGB1 were quantified using a commercially available rat HMGB1 ELISA kit (IBL, Hamburg, Germany) according to manufacturer's instructions and as described previously (14).…”

Toll-like Receptors in the Vascular System: Sensing the Dangers Within

“…TLR4 significantly contributes to the etiology of vascular dysfunction and high blood pressure in various experimental models of hypertension, such as the spontaneously hypertensive rat (SHR) and rats with angiotensin II-induced hypertension (De Batista et al, 2014;Hernanz et al, 2015). Similarly, TLR4 plays a role in paraventricular nucleusmediated autonomic dysfunction in SHR (Dange et al, 2015) and in rats with angiotensin II-induced hypertension (Dange et al, 2014). Less is known about the contribution of TLR4 on hypertensive kidney dysfunction; however, renal denervation can significantly decrease myocardial TLR4 expression in SHR (Jiang et al, 2012), and angiotensin II upregulates TLR4 expression on mesangial cells (Wolf et al, 2006).…”

How does bacterial endotoxin influence gonadoliberin/gonadotropins secretion and action?

“…Also, the importance of TLR4 signalling in modulation of the centrally regulated processes was also proved in the study on rats. It was found that the blockade of TLR4 in the paraventricular nucleus of the hypothalamus delayed the progression of hypertension, reduced cardiac hypertrophy, attenuated proinflammatory cytokines synthesis, inducible nitric oxide (NO) synthase and norepinephrine levels as well as NFκB activity (Dange et al, 2015).…”