Abstract
Exercise training (ExT) is beneficial for cardiovascular health, yet the central mechanism by which aerobic ExT attenuates the hypertensive responses remains unclear. Activation of pro-inflammatory cytokines (PICs) in the hypothalamic paraventricular nucleus (PVN) is important for the sympathoexcitation and hypertensive response. We thus hypothesized that aerobic ExT can decrease the blood pressure of hypertensive rats by reducing the levels of PICs through TLR4/MyD88/NF-κB signaling within the PVN. To examine this hypothesis, two-kidney-one-clip (2K1C) renovascular hypertensive rats were assigned to two groups: sedentary or exercise training and examined for 8 weeks. At the same time, bilateral PVN infusion of vehicle or TAK242, a TLR4 inhibitor, was performed on both groups. As a result, the systolic blood pressure (SBP), renal sympathetic nerve activity (RSNA) and plasma levels of norepinephrine (NE), epinephrine (EPI) were found significantly increased in 2K1C hypertensive rats. These rats also had higher levels of Fra-like activity, NF-κB p65 activity, TLR4, MyD88, IL-1β and TNF-α in the PVN than SHAM rats. Eight weeks of ExT attenuated the RSNA and SBP, repressed the NF-κB p65 activity, and reduced the increase of plasma levels of NE, EPI, and the expression of Fra-like, TLR4, MyD88, IL-1β and TNF-α in the PVN of 2K1C rats. These findings are highly similar to the results in 2K1C rats with bilateral PVN infusions of TLR4 inhibitor (TAK242). This suggests that 8 weeks of aerobic ExT may decrease blood pressure in hypertensive rats by reducing the PICs activation through TLR4/MyD88/NF-κB signaling within the PVN, and thus delays the progression of 2K1C renovascular hypertension.
Highlights
Hypertension is a complex disease and a risk factor for many other cardiovascular diseases
The novel finding of the present study are that: (i) The toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling was activated in the paraventricular nucleus of hypothalamic (PVN) in 2K1C renovascular hypertensive rats, and microinjection of TAK242 into the PVN inhibited TLR4/MyD88/NF-κB signaling and attenuated Systolic blood pressure (SBP); (ii) 8 weeks of aerobic exercise training significantly down-regulated TLR4/MyD88/NF-κB signaling transduction, down-regulated tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) protein expression in the PVN, reduced renal sympathetic nerve activity (RSNA), and attenuated hypertensive response of 2K1C hypertensive rats
It was reported that acute lipopolysaccharide (LPS)induced TLR4 activation within the PVN contributes to excessive sympathetic activity (Masson et al, 2015a; Sun et al, 2019), and injection of TLR4 viral inhibitory peptide into the PVN suppresses the RSNA in the spontaneously hypertensive rats (Dange et al, 2015)
Summary
Hypertension is a complex disease and a risk factor for many other cardiovascular diseases. Abundant evidences suggest that the paraventricular nucleus of hypothalamic (PVN) functions as a pivotal role in the patho- and physio-logy of hypertension (Kang et al, 2009; Wang et al, 2016; Bai et al, 2017; Li et al, 2019). PICs in the PVN is recognized as a major cause of elevating renal sympathetic nerve activity (RSNA) in hypertension. Exercise training (ExT) has been reported to be beneficial to patients suffering from hypertension when used as a supplement to pharmaceutical antihypertensive therapies (Nogueira-Ferreira et al, 2016). Research in athletes (Caselli et al, 2017), patients (Nascimento et al, 2017; Liu et al, 2018) and animals (Masson et al, 2015b; Rocha et al, 2016) suggests that it’s beneficial in the treatment of hypertension. ExT can effectively down-regulate the PICs in the PVN, enhance the
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