Exercise Training Attenuates Hypertension Through TLR4/MyD88/NF-κB Signaling in the Hypothalamic Paraventricular Nucleus

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.

Scoparone alleviates hepatic fibrosis by inhibiting the TLR‐4/NF‐κB pathway

“…To further confirm the SCO‐mediated suppression of the TLR‐4/NF‐κB pathway as well as downstream targets, TAK‐242 was used as an inhibitor of TLR‐4. To this end, Qi et al, (2019) infused TAK‐242 into the bilateral paraventricular nucleus (PVN) of 2K1C rats, whose expression of p‐NF‐κB, TLR‐4, and MyD88 was inhibited. Similarly, Lian et al, utilized TAK‐242 to downregulate TLR‐4, thereby reducing inflammation and fibrosis in diabetic nephropathy (Lian et al, 2019).…”

Paraventricular Nucleus Infusion of Oligomeric Proantho Cyanidins Improves Renovascular Hypertension

“…Experiments were performed on seven-week-old male Sprague-Dawley rats weighing between 180 and 220 g. The rats were housed with a 12 h light/dark cycle and ad libitum access to standard rat chow and water ( Zhu et al, 2009 ; Qi et al, 2019 ). The experiments were approved by the Animal Care and Use Committee of Xi’an Jiaotong University and conformed to the Guidelines for the Care and Use of Experimental Animals of the United States National Institutes of Health (NIH Publication No.…”

Apigenin Improves Hypertension and Cardiac Hypertrophy Through Modulating NADPH Oxidase-Dependent ROS Generation and Cytokines in Hypothalamic Paraventricular Nucleus

“…We collected the data between 8:30 and 12: 30 a.m. The specific method and subsequent data analysis have been described previously [12]. Briefly, unanesthetized rats were warmed to an ambient temperature of 30 °C by placing them in a holding device mounted on a thermostatically controlled warming plate so that sensor of Recording System can capture the sphygmus from the expanded tail blood vessels.…”

“…The RNA concentration and purity were checked spectrophotometrically by the 260/280 ratio. Reverse transcription was accomplished using a high-capacity cDNA reverse transcription kit (RR047, TaKaRa) and 1 μg RNA was used as the template as previously reported [12,33,34] (Table 1).…”

“…An excessive inflammatory response is well-recognized in affecting the severity and progression of hypertension-induced tissue and target organ injury [10,11]. In addition, overactivation of the brain renin-angiotensin system (RAS), ROS, the level of proinflammatory cytokines and the imbalance of neurotransmitters in the PVN are major contributors to sympathetic output in various models of hypertension [12][13][14]. Accumulating evidence has suggested Angiotensin (Ang) II, the main RAS effector peptide, can trigger significant upsurges in proinflammatory cytokines and ROS [15][16][17].…”