Hong-Bao Li

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

AIMS To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin-angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. METHODS AND RESULTS Male Sprague-Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91(phox) (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1 beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91(phox), ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. CONCLUSION These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension.

Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension.

The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10μg/h) or vehicle via osmotic minipump for 4weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91(phox)) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM.

Central blockade of salusin β attenuates hypertension and hypothalamic inflammation in spontaneously hypertensive rats

Salusin β is a multifunctional bioactive peptide and is considered as a promising candidate biomarker for predicting atherosclerotic cardiovascular diseases. The present study was designed to investigate the roles and mechanisms of salusin β in the paraventricular nucleus (PVN) in attenuating hypertension and hypothalamic inflammation and whether central salusin β blockade has protective effects in essential hypertension. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used in this study. The rats were chronic PVN infusion either specific salusin β blocker, antisalusin β IgG (SIgG), or control IgG (CIgG) for 2 weeks. Hypertensive rats had significantly increased salusin β expression compared with normotensive rats. Central blockade of salusin β attenuated hypertension, reduced circulating norepinephrine (NE) levels, and improved cardiac hypertrophy and function in hypertensive rats. Salusin β blockade significantly reduced proinflammatory cytokines (PICs), nuclear factor-kappa B (NF-κB) activity, reactive oxygen species (ROS) levels, and altered renin-angiotensin system (RAS) components in the PVN of hypertensive rats. These findings suggest that the beneficial effects of salusin β blockade in essential hypertension are possibly due to down-regulate of inflammatory molecules and ROS in the PVN.

Alpha lipoic acid supplementation attenuates reactive oxygen species in hypothalamic paraventricular nucleus and sympathoexcitation in high salt-induced hypertension.

AIMS High salt-induced oxidative stress plays an important role in the development of hypertension. Alpha lipoic acid (ALA) is extensively recognized as having a powerful superoxide inhibitory property. In this study, we determined whether ALA supplementation attenuates oxidative stress in hypothalamic paraventricular nucleus (PVN), decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by cross-talking with renin-angiotensin system (RAS) and pro-inflammatory cytokines (PICs). METHODS Male Wistar rats were administered a normal-salt diet (NS, 0.3% NaCl) or a high-salt diet (HS, 8.0% NaCl) for 8 weeks. These rats received ALA (60mg/kg) dissolved in vehicle (0.9% saline) or an equal voleme of vehicle, by gastric perfusion for 9 weeks. RESULTS High salt intake resulted in higher renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP). These rats also had higher levels of superoxide, gp91(phox), gp47(phox) (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), angiotensin II type1 receptor (AT1-R), interleukin-1beta (IL-1β), interleukin-6 (IL-6), and lower levels of interleukin-10 (IL-10) and copper/zinc superoxide dismutase (Cu/Zn-SOD) than control animals. Treatment with ALA significantly attenuated the levels of superoxide, gp91(phox), gp47(phox), ACE, AT1-R, IL-1β and IL-6, increased the levels of IL-10 and Cu/Zn-SOD, and decreased MAP and RSNA compared with high-salt induced hypertensive rats. The mRNA expression of gp47(phox) and gp91(phox) are in accordance with their protein expression. CONCLUSION These findings suggest that supplementation of ALA obviously decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by improving the superoxide inhibitory property, suppressing the activation of RAS and restoring the balance between pro- and anti-inflammatory cytokines in the PVN.

Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension

Reactive oxygen species (ROS) in the brain plays an important role in the progression of hypertension and hydrogen peroxide (H2O2) is a major component of ROS. The aim of this study is to explore whether endogenous H2O2 changed by polyethylene glycol-catalase (PEG-CAT) and aminotriazole (ATZ) in the hypothalamic paraventricular nucleus (PVN) regulates neurotransmitters, renin-angiotensin system (RAS), and cytokines, and whether subsequently affects the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in high salt-induced hypertension. Male Sprague-Dawley rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 10 weeks. Then rats were treated with bilateral PVN microinjection of PEG-CAT (0.2 i.u./50nl), an analog of endogenous catalase, the catalase inhibitor ATZ (10nmol/50nl) or vehicle. High salt-fed rats had significantly increased MAP, RSNA, plasma norepinephrine (NE) and pro-inflammatory cytokines (PICs). In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), interleukin-1beta (IL-1β), glutamate and NE, and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN than normal diet rats. Bilateral PVN microinjection of PEG-CAT attenuated the levels of RAS and restored the balance of neurotransmitters and cytokines, while microinjection of ATZ into the PVN augmented those changes occurring in hypertensive rats. Our findings demonstrate that ROS component H2O2 in the PVN regulating MAP and RSNA are partly due to modulate neurotransmitters, renin-angiotensin system, and cytokines within the PVN in salt-induced hypertension.

Oleuropein improves mitochondrial function to attenuate oxidative stress by activating the Nrf2 pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats.

&NA; Hypertension is associated with increased reactive oxygen species (ROS) production in the paraventricular nucleus (PVN) of the hypothalamus. Oleuropein (OL) has a variety of biochemical roles, including antihypertensive and antioxidative functions. However, there have been few reports on the effects of OL on oxidative stress in the PVN on hypertension. In spontaneously hypertensive rats (SHR), eight‐week administration of 60 mg/kg/day of OL significantly reduced blood pressure, pro‐inflammatory cytokines and the expression of components of the renin‐angiotensin system (RAS) compared with SHR rats treated with saline. Concomitantly, OL inhibited superoxide, and increased the antioxidant defense system in the PVN of SHR. We also found that OL increased mitochondrial biogenesis through mtDNA, PGC‐1&agr;, Complex II and Complex IV expression and regulated mitochondrial dynamics through the fusion‐related protein Mfn2 and fision‐related protein DRP1 to attenuate mitochondrial impairment. Furthermore, the phase II enzyme levels of Nrf2 and its downstream proteins NQO‐1 and HO‐1 were all markedly increased in the PVN of the OL‐treated SHR group compared with the saline‐treated SHR rats. Our findings demonstrate that OL administration can protect the PVN of the hypothalamus from oxidative stress by improving mitochondrial function through the activation of the Nrf2‐mediated signaling pathway. HighlightsOxidative stress in the hypothalamus is associated with hypertension.Oleuropein supplementation attenuated hypertension symptoms in SHR.Oleuropein inhibited PVN oxidative stress in SHR.Oleuropein attenuated PVN mitochondrial impairment in SHR.The effect of oleuropein on the PVN may occur via the activation of the Nrf2 pathway.

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

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.

Chronic infusion of epigallocatechin-3-O-gallate into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation by restoring neurotransmitters and cytokines

Reactive oxygen species (ROS) in the brain are involved in the pathogenesis of hypertension. Epigallocatechin-3-O-gallate (EGCG), one of the active compounds in green tea, has anti-oxidant, anti-inflammatory and vascular protective properties. This study was designed to determine whether chronic infusion of EGCG into the hypothalamic paraventricular nucleus (PVN) attenuates ROS and sympathetic activity and delays the progression of hypertension by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and decreasing nuclear factor-kappa B (NF-κB) activity, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar-Kyoto (WKY) rats and SHR received bilateral PVN infusion of EGCG (20μg/h) or vehicle via osmotic minipumps for 4 weeks. SHR showed higher mean arterial pressure, plasma proinflammatory cytokines and circulating norepinephrine (NE) levels compared with WKY rats. SHR also had higher PVN levels of the subunit of NAD(P)H oxidase (gp91phox), ROS, tyrosine hydroxylase, and PICs; increased NF-κB activity; and lower PVN levels of interleukin-10 (IL-10) and 67kDa isoform of glutamate decarboxylase (GAD67) than WKY rats. PVN infusion of EGCG attenuated all these changes in SHR. These findings suggest that SHR have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN. Chronic inhibition of ROS in the PVN restores the balance of neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive response and sympathetic activity.

Blockade of Salusin-β in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats.

Abstract: Salusin-&bgr;, a multifunctional bioactive peptide, is considered as a promising candidate biomarker for predicting cardiovascular diseases. This study was designed to determine whether inhibition of salusin-&bgr; in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by restoring neurotransmitters and cytokines. Male Sprague Dawley rats were fed with a normal salt diet (NS, 0.3%) or a high salt diet (HS, 8%) for 8 weeks to induce hypertension. Then, these rats received bilateral PVN infusion of a specific salusin-&bgr; blocker, antisalusin-&bgr; IgG (SIgG), or control IgG (CIgG) for 2 weeks. HS rats exhibited higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/bodyweight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and messenger RNA levels of cardiac atrial natriuretic peptide (ANP), and &bgr;-myosin heavy chain. Compared with NS rats, HS rats had higher levels of glutamate, norepinephrine, tyrosine hydroxylase, proinflammatory cytokines, and lower levels of gamma-aminobutyric acid, interleukin 10, and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN, and higher plasma levels of proinflammatory cytokines. Chronic PVN infusion of SIgG attenuated all these changes in HS rats. Our findings suggest that HS rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between proinflammatory and anti-inflammatory cytokines in the PVN; and chronic inhibition of salusin-&bgr; in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy.

Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension

Hydrogen sulfide (H2S) is an important gaseous signaling molecule in neuro-modulation, anti-inflammatory, anti-oxidant and anti-hypertensive effects. The paraventricular nucleus (PVN) is a major integrative nucleus in regulating BP and SNA. The aim of this study is to explore whether endogenous or exogenous H2S changed by hydroxylamine hydrochloride (HA) or GYY4137 infused in the PVN affects RSNA and MAP by regulating oxidative stress or the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines in high salt-induced hypertensive rats. Male Dahl rats were fed by high-salt or normal-salt diet. At the end of the 4th week, GYY4137, HA or vehicle was microinjected into bilateral PVN for 6 weeks. The levels of MAP, HR, plasma norepinephrine (NE), reactive oxygen species (ROS), NOX2, NOX4 and IL-1β were increased significantly in high salt-induced hypertensive rats. Higher levels of these parameters were detected in the group treated by HA, but lower levels in the GYY4137 group. The trends of H2S, CBS, IL-10 and Cu/Zn SOD were opposite to the parameters described above. These findings suggest that endogenous or exogenous H2S in the PVN attenuates sympathetic activity and hypertensive response, which are partly due to decrease of ROS and PICs within the PVN in high salt-induced hypertension.