TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension

Jun 14, 2016Toxicology and applied pharmacology

Telmisartan’s effects on high blood pressure may involve immune signaling and metabolism control in the brain’s blood pressure center

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Abstract

Hypertensive rats showed significantly higher levels of angiotensin II type 1 receptors and lower levels of PPAR-γ in the hypothalamic paraventricular nucleus.

Treatment with the AT1-R antagonist telmisartan reduced mean arterial pressure in hypertensive rats.
Telmisartan treatment improved cardiac hypertrophy and decreased levels of pro-inflammatory cytokines in hypertensive rats.
The reduction in inflammation was associated with decreased levels of TLR4, MyD88, and NF-κB in the hypothalamic paraventricular nucleus.
Increased levels of PPAR-γ were observed in the hypothalamic paraventricular nucleus following telmisartan treatment in hypertensive rats.
Similar effects were not observed in normotensive rats, indicating a specific response in hypertensive conditions.

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Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10μg/h), or losartan (LOS, 20μg/h), or the PPAR-γ antagonist GW9662 (GW, 100μg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension.

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TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension

Abstract

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