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1.
Neurosci Bull ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989424

RESUMO

Chemical stimulation of the kidney increases sympathetic activity and blood pressure in rats. The hypothalamic paraventricular nucleus (PVN) is important in mediating the excitatory renal reflex (ERR). In this study, we examined the role of molecular signaling in the PVN in mediating the capsaicin-induced ERR and sympathetic activation. Bilateral PVN microinjections were performed in rats under anesthesia. The ERR was elicited by infusion of capsaicin into the cortico-medullary border of the right kidney. The reflex was evaluated as the capsaicin-induced changes in left renal sympathetic nerve activity and mean arterial pressure. Blockade of angiotensin type 1 receptors with losartan or inhibition of angiotensin-converting enzyme with captopril in the PVN abolished the capsaicin-induced ERR. Renal infusion of capsaicin significantly increased NAD(P)H oxidase activity and superoxide anion production in the PVN, which were prevented by ipsilateral renal denervation or microinjection of losartan into the PVN. Furthermore, either scavenging of superoxide anions or inhibition of NAD(P)H oxidase in the PVN abolished the capsaicin-induced ERR. We conclude that the ERR induced by renal infusion of capsaicin is mediated by angiotensin type 1 receptor-related NAD(P)H oxidase activation and superoxide anion production within the PVN.

2.
Neurosci Bull ; 36(2): 143-152, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31392556

RESUMO

Sympathetic activation and the kidney play critical roles in hypertension and chronic heart failure. The role of the kidney in sympathetic activation is still not well known. In this study, we revealed an excitatory renal reflex (ERR) in rats induced by chemical stimulation of the kidney that regulated sympathetic activity and blood pressure. The ERR was induced by renal infusion of capsaicin, and evaluated by the changes in renal sympathetic outflow, blood pressure, and heart rate. Renal infusion of capsaicin dose-dependently increased the contralateral renal sympathetic nerve activity, mean arterial pressure, and heart rate. Capsaicin in the cortico-medullary border had greater effects than in the cortex or medulla. Intravenous infusion of capsaicin had no significant effects. The effects of renal infusion of capsaicin were abolished by ipsilateral renal denervation, but were not affected by bilateral sinoaortic denervation. Renal infusion of capsaicin increased the ipsilateral renal afferent activity. The ERR was also induced by renal infusion of bradykinin, adenosine, and angiotensin II, but not by ATP. Renal infusion of capsaicin increased c-Fos expression in the paraventricular nucleus (PVN) of hypothalamus. Lesion of neurons in the PVN with kainic acid abolished the capsaicin-induced ERR. These findings indicate that chemical stimulation of kidney causes an excitatory reflex, leading to sympathetic activation, pressor response, and accelerated heart rate. The PVN is an important central nucleus in the pathway of the ERR.

3.
Neuroendocrinology ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31671427

RESUMO

BACKGROUND: Inflammation and oxidative stressplay important roles in energy imbalance and its complications.Recent research indicates that hypothalamic inflammation may contribute to the pathogenesis of metabolic syndrome and cardiac dysfunction, but the mechanisms remain unclear. We hypothesized that suppression of proinflammatory pathway of IKKß/NF-κBin the hypothalamuscan improve energy balance and cardiac function in type 2 diabetic (T2D)rats. METHODS AND RESULTS: Normal rats and T2D rats received bilateral hypothalamic arcuate nucleus (ARC) infusions of IKKß inhibitor SC-514 or vehicle via osmotic minipump.Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were used to investigate the outcomes of inhibition of the hypothalamic IKKß. Echocardiography and glucometer were used for measuring cardiac function and blood glucose,respectively. Blood samples were collected for the evaluation of circulating proinflammatory cytokines (PICs). Heart was harvested for cardiacmorphology evaluations. The ARC was harvested and analyzed for IKKß, NF-κB, PICs, reactive oxygen species (ROS) and NAD(P)H (gp91phox,p47phox) oxidase activitylevels and neuropeptides.Compared with normal rats, T2D rats were characterized by hyperglycaemia, hyperinsulinemia, glucose intolerance, cardiac dysfunction, as well as higher ARC levels of IKKß, NF-κB, PICs, ROS, gp91phox and p47phox. ARC infusion of IKKß inhibitor SC-514 attenuated all these changes in T2D rats, but not in normal rats. CONCLUSIONS: Our results indicate that hypothalamic IKKß/NF-κB pathway plays a key role in modulatingenergy imbalance and cardiac dysfunction, suggesting its potential therapeutic role during type 2diabetes.

4.
Neurosci Bull ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641986

RESUMO

Toll-like receptor 4 (TLR4) and cellular Src (c-Src) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-Src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-Src, while microinjection of a c-Src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a long-term high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-Src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen species. Therefore, inhibiting central c-Src activity may be a new target for treating hypertension.

5.
J Nutr Biochem ; 72: 108212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473513

RESUMO

Migration of vascular smooth muscle cell (VSMC) plays a critical role in the pathophysiology of hypertension and several other vascular diseases. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a bioactive constituent from Curcuma longa, is commonly used as a spice, food additive or dietary pigment. It has several health benefits including antioxidant, anti-inflammatory and anticancer properties. This study examined the roles of curcumin in VSMC migration in hypertension and underlying mechanism. VSMC was isolated and prepared from thoracic aorta of Wistar-Kyoto rats and spontaneously hypertensive rats (SHR). VSMC migration was evaluated with Boyden chamber assay and wound-healing assay. Curcumin attenuated VSMC migration, inhibited nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression and reduced interleukin (IL)-1ß concentration in VSMC of SHR, which were similar to the effects of NLRP3 knockdown on IL-1ß concentration and VSMC migration. Curcumin inhibited NFκB activation in VSMC of SHR, which was similar to the effects of NFκB inhibitor BAY11-7082 on NFκB activation. In another in vitro model of rat VSMC migration, curcumin also inhibited angiotensin II-induced VSMC migration, NFκB activation, NLRP3 expression and IL-1ß production. Intragastric administration of curcumin in SHR attenuated hypertension and reduced NFκB activation, NLRP3 and matrix metalloproteinase-9 expressions and aortic media thickness. These results indicate that curcumin inhibits VSMC migration via inhibiting NFκB-mediated NLRP3 expression in VSMC of SHR or in angiotensin II-treated VSMC. Curcumin attenuates hypertension, vascular inflammation and vascular remodeling in SHR.

6.
J Transl Med ; 17(1): 256, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391086

RESUMO

BACKGROUND: The adipose afferent reflex (AAR), a sympatho-excitatory reflex, can promote the elevation of sympathetic nerve activity (SNA) and blood pressure (BP). Inflammation in the paraventricular nucleus (PVN) involves sympathetic abnormality in some cardiovascular diseases such as hypertension. This study was designed to explore the effects of tumor necrosis factor alpha (TNFα) in the PVN on the AAR and SNA in rats with obesity-related hypertension (OH) induced by a high-fat diet for 12 weeks. METHODS: Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded in anesthetized rats, and their responses to capsaicin (CAP) stimulation of the right inguinal white adipose tissue were used to evaluate the AAR. RESULTS: Compared to the control rats, the systolic blood pressure (SBP), plasma norepinephrine (NE, indicating SNA) and TNFα levels, TNFα mRNA and protein levels, reactive oxygen species (ROS) content and NADPH oxidase activity in the PVN were significantly elevated in rats with OH. TNFα in the PVN markedly enhanced sympathoexcitation and AAR. Moreover, the enhancement of AAR caused by TNFα can be significantly strengthened by the pretreatment of diethyldithiocarbamate (DETC), a superoxide dismutase inhibitor, but attenuated by TNF-α receptor antagonist R-7050, superoxide scavenger PEG-SOD and NADPH oxidase inhibitor apocynin (Apo) in rats with OH. Acute microinjection of TNF-α into the PVN significantly increased the activity of NADPH oxidase and ROS levels in rats with OH, which were effectively blocked by R-7050. Furthermore, our results also showed that the increased levels of ROS, TNFα and NADPH oxidase subunits mRNA and protein in the PVN of rats with OH were significantly reversed by pentoxifylline (PTX, 30 mg/kg daily ip; in 10% ethanol) application, a cytokine blocker, for a period of 5 weeks. PTX administration also significantly decreased SBP, AAR and plasma NE levels in rats with OH. CONCLUSIONS: TNFα in the PVN modulates AAR and contributes to sympathoexcitation in OH possibly through NADPH oxidase-dependent ROS generation. TNFα blockade attenuates AAR and sympathoexcitation that unveils TNFα in the PVN may be a possible therapeutic target for the intervention of OH.

7.
Neuropharmacology ; 158: 107709, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310777

RESUMO

To investigate the roles of mu opioid receptors (MORs) in paraventricular nucleus of the hypothalamus (PVN) on ejaculation and its underlying mechanism in the rats, we performed copulation behavioral testing and acute experiments. During the acute experiments, mean arterial pressure (MAP), heart rate (HR), bulbospongiosus muscle-electromyogram (BSM-EMG) and pressure of vas deferens (PVD) were all recorded. The expression levels and distributions of opioid receptors were also assessed in PVN of male rats. Moreover, adeno-associated virus type 1 (AAV1) was microinjected into PVN to demonstrate whether there are direct projections from PVN to lumbar spinothalamic (LSt) cells. We found that microinjection of MOR agonist, D-A1a2-NM9-Phe4-Gly(ol)5enkephalin (DAGO), into the PVN prolonged the intromission latency and inhibited ejaculation (P = 0.0241, P = 0.0473, respectively), while the opposed results appeared in CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2, MOR antagonist) group (P = 0.0021, P = 0.0286, respectively). Moreover, DAGO caused a significant decrease in MAP and HR (P = 0.0065, P = 0.0030, respectively), and PVD decreased significantly after DAGO microinjection in PVN (P = 0.0383). CTAP not only blocked the effect of DAGO but also significantly increased MAP, HR and PVD (P = 0.0003, P = 0.0010, P = 0.0074, respectively). Meanwhile, a significant increase was observed in BSM-EMG activity after microinjecting of CTAP (P = 0.0022), accompanied by visible BSM contraction. Additionally, anterograde monosynaptic transneuronal tracer AAV1 labeling revealed that neurons in PVN projected directly to LSt cells in L3-4 spinal cord. These results indicate that MORs in PVN centrally mediate ejaculation by regulating the sympathetic outflow, which may be treated as a therapeutic target for ejaculation disorders in the future.

8.
Vascul Pharmacol ; 121: 106579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319161

RESUMO

Foam cell formation and monocytes adhesion are key events in pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) are an important origin of foam cells besides macrophages. Fibronectin type III domain containing protein 5 (FNDC5) is a protein, which induces browning of fat and attenuates glucose/lipid metabolic derangements in obese mice. The present study was designed to determine the roles of FNDC5 in inhibiting foam cell formation and monocyte adhesion in VSMCs and its underlying mechanisms. Oxidized low-density lipoprotein (oxLDL) was used to induce foam cell formation and monocyte adhesion in human aortic VSMCs. Foam cell formation was evaluated by intracellular lipid droplets, cholesterol contents, and mRNA levels of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT-1) and ATP binding cassette transporter A-1 (ABCA-1). Monocyte adhesion was evaluated by the number of monocytes adhered to VSMCs and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1). FNDC5 inhibited oxLDL-induced foam cell formation, monocyte adhesion, ABCA-1 mRNA downregulation, and ACAT-1, MCP-1 and VCAM-1 mRNA upregulation in VSMCs. It inhibited oxLDL-induced p65-NFκB nuclear translocation, NLRP3 upregulation, caspase-1 and IL-1ß production. Inhibition of NFκB with BMS-345541 or inhibition of NLRP3 inflammasome with MCC950 showed similar effects to FNDC5 in attenuating the oxLDL-induced foam cell formation, monocyte adhesion, and caspase-1 and IL-1ß production. The oxLDL-induced NLRP3 upregulation was prevented by BMS-345541 rather than MCC950. These results indicate that FNDC5 inhibits oxLDL-induced foam cell formation and monocyte adhesion in VSMCs via suppressing NFκB-mediated NLRP3 upregulation and IL-1ß production.

9.
Oxid Med Cell Longev ; 2019: 5018410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30805081

RESUMO

Proliferation and oxidative stress of vascular smooth muscle cells (VSMCs) contribute to vascular remodeling in hypertension and several major vascular diseases. B-cell lymphoma 6 (BCL6) functions as a transcriptional repressor. The present study is designed to determine the roles of BCL6 in VSMC proliferation and oxidative stress and underlying mechanism. Angiotensin (Ang) II was used to induce VSMC proliferation and oxidative stress in human VSMCs. Effects of BCL6 overexpression and knockdown were, respectively, investigated in Ang II-treated human VSMCs. Therapeutical effects of BCL6 overexpression on vascular remodeling, oxidative stress, and proliferation were determined in the aorta of spontaneously hypertensive rats (SHR). Ang II reduced BCL6 expression in human VSMCs. BCL6 overexpression attenuated while BCL6 knockdown enhanced the Ang II-induced upregulation of NADPH oxidase 4 (NOX4), production of reactive oxygen species (ROS), and proliferation of VSMCs. BCL6 expression was downregulated in SHR. BCL6 overexpression in SHR reduced NOX4 expression, ROS production, and proliferation of the aortic media of SHR. Moreover, BCL6 overexpression attenuated vascular remodeling and hypertension in SHR. However, BCL6 overexpression had no significant effects on NOX2 expression in human VSMCs or in SHR. We conclude that BCL6 attenuates proliferation and oxidative stress of VSMCs in hypertension.


Assuntos
Hipertensão/metabolismo , Hipertensão/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Hipertensão/fisiopatologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular/efeitos dos fármacos
10.
Phytomedicine ; 52: 216-224, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599901

RESUMO

BACKGROUND: Berberine (BBR), a Chinese traditional herbal medicine, has many pharmacologic benefits such as anti-inflammation and anti-oxidation. It is widely used in clinical treatment of cardiovascular diseases such as hypertension. However, the mechanism of how BBR attenuates hypertension through affecting central neural system is not clear. PURPOSE: This study was designed to determine whether chronic infusion of BBR into the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. METHODS: Two-kidney, one-clip (2K1C) renovascular hypertensive rats were randomly assigned and treated with bilateral PVN infusion of BBR (2µg/h) or vehicle (artificial cerebrospinal fluid) via osmotic minipumps for 28 days. RESULTS: 2K1C rats showed higher mean arterial pressure (MAP) and PVN Fra-like activity, plasma levels of norepinephrine (NE), PVN levels of NOX2, NOX4, Erk1/2 and iNOS, and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD). Chronic infusion of BBR reduced MAP, PVN Fra-like activity and plasma levels of NE, reduced NOX2, NOX4, Erk1/2, iNOS and induced Cu/Zn-SOD in the PVN. CONCLUSIONS: These results suggest that BBR attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway in 2K1C renovascular hypertensive rats.


Assuntos
Berberina/farmacologia , Hipertensão/tratamento farmacológico , Sistema de Sinalização das MAP Quinases , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Pressão Arterial , Masculino , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Norepinefrina/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismo
11.
Neurosci Bull ; 35(1): 47-56, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30328008

RESUMO

Angiotensin (Ang)-(1-7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1-7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1-7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1-7) in the PVN, through modulation of PICs and oxidative stress.


Assuntos
Angiotensina I/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Cloreto de Sódio na Dieta/farmacologia , Angiotensina I/metabolismo , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Fragmentos de Peptídeos/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
12.
Neurosci Bull ; 35(1): 57-66, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30426340

RESUMO

Metformin (MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension. This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus (PVN). Salt-sensitive rats received a high-salt (HS) diet to induce hypertension, or a normal-salt (NS) diet as control. At the same time, they received intracerebroventricular (ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure (MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity, reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in salt-sensitive hypertension via attenuating oxidative stress, inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.


Assuntos
Hipertensão/tratamento farmacológico , Metformina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Animais , Antioxidantes/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão/induzido quimicamente , Infusões Intraventriculares , Masculino , Metformina/administração & dosagem , Neurotransmissores/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Neurosci Bull ; 35(1): 34-46, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30276527

RESUMO

Intermedin/adrenomedullin-2 (IMD/AM2), a member of the calcitonin gene-related peptide/AM family, plays an important role in protecting the cardiovascular system. However, its role in the enhanced sympathoexcitation in obesity-related hypertension is unknown. In this study, we investigated the effects of IMD in the paraventricular nucleus (PVN) of the hypothalamus on sympathetic nerve activity (SNA), and lipopolysaccharide (LPS)-induced sympathetic activation in obesity-related hypertensive (OH) rats induced by a high-fat diet for 12 weeks. Acute experiments were performed under anesthesia. The dynamic alterations of sympathetic outflow were evaluated as changes in renal SNA and mean arterial pressure (MAP) in response to specific drugs. Male rats were fed a control diet (12% kcal as fat) or a high-fat diet (42% kcal as fat) for 12 weeks to induce OH. The results showed that IMD protein in the PVN was downregulated, but Toll-like receptor 4 (TLR4) and plasma norepinephrine (NE, indicating sympathetic hyperactivity) levels, and systolic blood pressure were increased in OH rats. LPS (0.5 µg/50 nL)-induced enhancement of renal SNA and MAP was greater in OH rats than in obese or control rats. Bilateral PVN microinjection of IMD (50 pmol) caused greater decreases in renal SNA and MAP in OH rats than in control rats, and inhibited LPS-induced sympathetic activation, and these were effectively prevented in OH rats by pretreatment with the AM receptor antagonist AM22-52. The mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) inhibitor U0126 in the PVN partially reversed the LPS-induced enhancement of SNA. However, IMD in the PVN decreased the LPS-induced ERK activation, which was also effectively prevented by AM22-52. Chronic IMD administration resulted in significant reductions in the plasma NE level and blood pressure in OH rats. Moreover, IMD lowered the TLR4 protein expression and ERK activation in the PVN, and decreased the LPS-induced sympathetic overactivity. These results indicate that IMD in the PVN attenuates SNA and hypertension, and decreases the ERK activation implicated in the LPS-induced enhancement of SNA in OH rats, and this is mediated by AM receptors.


Assuntos
Adrenomedulina/metabolismo , Hipertensão/etiologia , Neuropeptídeos/metabolismo , Receptores de Adrenomedulina/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Lipopolissacarídeos/farmacologia , Masculino , Obesidade/complicações , Ratos Sprague-Dawley , Receptores de Adrenomedulina/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo
14.
Int J Cardiol ; 280: 142-151, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30581101

RESUMO

OBJECTIVE: Sustained hypertension is a major cause of heart failure in aging hypertensive patients. Salusin ß, a novel bioactive peptide of 20 amino acids, has been reported to participate in various cardiovascular diseases, including hypertension. We therefore hypothesized that central knockdown of salusin ß might be effective for hypertension-induced heart failure treatment. METHODS AND RESULTS: Eighteen-month-old male aged spontaneously hypertensive rats (SHR) with heart failure and WKY rats were microinjected with either a specific adenoviral vector encoding salusin ß shRNA (Ad-Sal-shRNA) or a scramble shRNA (Ad-Scr-shRNA) in the hypothalamic paraventricular nucleus (PVN) for 4 weeks. Radiotelemetry and echocardiography were used for measuring blood pressure and cardiac function, respectively. Blood samples and heart were harvested for evaluating plasma norepinephrine, tyrosine hydroxylase, and cardiac morphology, respectively. The mesenteric arteries were separated for measurement of vascular responses. The PVN was analyzed for salusin ß, proinflammatory cytokines (PICs), mitogen-activated protein kinase (MAPK), NF-κB, and reactive oxygen species (ROS) levels. Compared with normotensive rats, aging SHR with heart failure had dramatically increased salusin ß expression. Silencing salusin ß with Ad-Sal-shRNA attenuated arterial pressure and improved autonomic function, cardiac and vascular dysfunction in aging SHR with heart failure, but not in aging WKY rats. Knockdown of salusin ß significantly reduced paraventricular nucleus PICs levels, MAPK and NF-κB activity, and ROS levels in aging SHR with heart failure. CONCLUSION: These data demonstrate that in aging SHR, the heart failure that was developed during the end stage of hypertension could be ameliorated by silencing salusin ß.


Assuntos
Envelhecimento/metabolismo , Insuficiência Cardíaca/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Técnicas de Silenciamento de Genes/métodos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Núcleo Hipotalâmico Paraventricular/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
15.
Hypertension ; 72(4): 881-888, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354715

RESUMO

Migration of vascular smooth muscle cells (VSMCs) is pivotal for vascular remodeling in hypertension. Vascular adventitial fibroblasts (AFs) are important in the homeostasis of vascular structure. This study is designed to investigate the roles of AF exosomes (AFE) in VSMC migration and underling mechanism. Primary VSMCs and AFs were obtained from the aorta of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. VSMC migration was evaluated with Boyden chamber assay and wound healing assay. AFE from WKY rats and SHR were isolated and identified. AFE from SHR promoted but AFE from WKY rats had no significant effect on VSMC migration. The effects of AFE on VSMC migration were prevented by an exosome inhibitor GW4869, an AT1R (Ang II [angiotensin II] type 1 receptor) antagonist losartan, or an inhibitor of ACE (angiotensin-converting enzyme) captopril. ACE contents and activity were much higher in AFE from SHR than those from WKY rats. There were no significant difference in Ang II and AT1R mRNA and protein levels between AFE from SHR and AFE from WKY rats. AFE from SHR increased Ang II and ACE contents and ACE activity in VSMCs of WKY rats and SHR. The changes of Ang II contents and ACE activity were prevented by captopril. ACE knockdown in AFs reduced ACE contents and activity in AFE from SHR and inhibited AFE-induced migration of VSMCs of WKY rats and those of SHR. These results indicate that exosomes from AFs of SHR transfer ACE to VSMCs, which increases Ang II levels and activates AT1R in VSMCs and thereby promotes VSMC migration.


Assuntos
Túnica Adventícia , Exossomos , Fibroblastos , Hipertensão , Peptidil Dipeptidase A , Remodelação Vascular , Túnica Adventícia/efeitos dos fármacos , Túnica Adventícia/fisiologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Compostos de Anilina/farmacologia , Animais , Compostos de Benzilideno/farmacologia , Captopril/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Técnicas de Silenciamento de Genes/métodos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Losartan/farmacologia , Músculo Liso Vascular/fisiologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologia
16.
Cell Physiol Biochem ; 48(1): 227-236, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30007970

RESUMO

BACKGROUND/AIMS: Fibronectin type III domain-containing 5 (FNDC5) protein is involved in the beneficial effects of exercise on metabolism. FNDC5 attenuates hepatic steatosis induced by high fat diet (HFD). Here, we examined the effects of FNDC5 on liver fibrosis and underline mechanisms. METHODS: Experiments were carried out on wild-type and FNDC5-/- mice, primary mouse hepatic stellate cells (HSCs) and human hepatic stellate cell line (LX-2). The mice were fed with HFD for 6 months to induce liver fibrosis. Oxidized low density lipoprotein (oxLDL) were used to induce the activation of hepatic stellate cells and fibrosis in mouse HSCs and human LX-2 cells. H&E, Masson's trichrome staining and Sirius red staining were used for liver sections. Protein and mRNA expressions were evaluated with Western blot and RT-PCR, respectively. RESULTS: FNDC5 deficiency aggravated the HFD-induced liver fibrosis and HSCs activation in mice. It exacerbated the HFD-induced inhibition of AMPK phosphorylation, upregulation of connective tissue growth factor (CTGF) and transforming growth factor-ß (TGF-ß), and deposition of extracellular matrix (ECM) in liver of mice. Administration of FNDC5 attenuated oxLDL-induced AMPK deactivation, HSCs activation, CTGF and TGF-ß upregulation and ECM deposition in mouse HSCs. The beneficial effects of FNDC5 on oxLDL-induced AMPK dephosphorylation, HSCs activation and ECM deposition were prevented by the inhibition of AMPK with compound C in human LX-2 cells. However, the effects of FNDC5 on hepatic fibrosis in vivo in this study cannot be distinguished from its effects on adiposity and hepatic steatosis. CONCLUSIONS: FNDC5 deficiency aggravates HFD-induced liver fibrosis in mice. FNDC5 plays beneficial roles in attenuating liver fibrosis via AMPK phosphorylation-mediated inhibition of HSCs activation.


Assuntos
Fibronectinas/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Células Cultivadas , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Dieta Hiperlipídica , Matriz Extracelular/metabolismo , Fibronectinas/genética , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Lipoproteínas LDL/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
17.
Cell Physiol Biochem ; 48(3): 1369-1381, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30048986

RESUMO

BACKGROUND/AIMS: Exercise training (ExT) was associated with cardiovascular diseases including hypertension. The rostral ventrolateral medulla (RVLM) is a key region for central control of blood pressure and sympathetic nerve activity. Therefore, this study aimed to investigate the mechanisms within RVLM that can influence exercise training induced effects in salt-induced hypertension. METHODS: Male Wistar rats were fed with a normal salt (0.3%) (NS) or a high salt (8%) (HS) diet for 12 weeks to induce hypertension. Then these rats were given moderate-intensity ExT for a period of 12 weeks. RVLM was used to determine glutamate and gamma-aminobutyric acid (HPLC), phosphorylated IKKß, Fra-LI, 67-kDa isoform of glutamate decarboxylase (GAD67), proinflammatory cytokines (PIC) and NADPH-oxidase (NOX) subunits expression (Immunohistochemistry and Immunofluorescence, Western blotting). PIC and NF-κB p65 activity in the plasma were evaluated by ELISA studies. Renal sympathetic nerve activity (RSNA) was recorded and analyzed using the PowerLab system. RESULTS: High salt diet resulted in increased mean arterial pressure and cardiac hypertrophy. These high salt diet rats had higher RVLM levels of glutamate, PIC, phosphorylated IKKß, NF-κB p65 activity, Fra-LI, superoxide, NOX-2 (gp91phox) and 4, and lower RVLM levels of gamma-aminobutyric acid and GAD67, and higher plasma levels of PIC, norepinephrine, and higher RSNA. ExT attenuated these changes in salt-induced hypertensive rats. CONCLUSIONS: These findings suggest that high salt diet increases the activity of NF-κB and the levels of PIC and oxidative stress, and induces an imbalance between excitatory and inhibitory neurotransmitters in the RVLM. ExT attenuates hypertension and cardiac hypertrophy partially mediated by attenuating oxidative stress and modulating neurotransmitters in the RVLM.


Assuntos
Pressão Sanguínea , Citocinas/metabolismo , Hipertensão/fisiopatologia , Bulbo/fisiopatologia , Neurotransmissores/metabolismo , Estresse Oxidativo , Condicionamento Físico Animal , Animais , Citocinas/análise , Terapia por Exercício , Hipertensão/metabolismo , Hipertensão/terapia , Rim/inervação , Rim/fisiopatologia , Masculino , Bulbo/metabolismo , NADPH Oxidases/análise , NADPH Oxidases/metabolismo , Neurotransmissores/análise , Ratos Wistar , Cloreto de Sódio na Dieta/metabolismo , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia
18.
Am J Hypertens ; 31(9): 1013-1023, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-29767672

RESUMO

BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in the progression of cardiovascular disease, including hypertension. However, the role of TLR4 in the development of prehypertension is uncertain. METHODS: Prehypertensive rats were treated with 8% salt for 12 weeks to induce prehypertension. These rats were then given either TAK-242 selective TLR4 blocker, or vehicle by bilateral micro-injection to the paraventricular nucleus (PVN). Blood pressure (BP) and renal sympathetic nerve activity were recorded. PVN expression of TLR4, myeloid differentiation factor 88 (Myd88), nuclear factor-kappa B (NF-κB) p65, proinflammation cytokines (PICs), interleukin (IL)-1ß, IL-6, tumor necrosis factor-alpha (TNF-α), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NADPH oxidase 4 (NOX4), Cu/Zn superoxide dismutase (SOD) level, tyrosine hydroxylase, and 67 kDa isoform of glutamate decarboxylase (GAD67) were tested to determine the influence of TLR4 blockade. RESULTS: TLR4 expression increased significantly in the PVN of high-salt groups with a corresponding increase in reactive oxygen species (ROS) and PICs. TLR4 blockade significantly reduced the signaling molecules downstream TLR4 and the expression of TNF-α, IL-6, IL-1ß, decreased ROS, NOX2, NOX4 level, increased Cu/Zn-SOD, re-balanced neurotransmitters, and regulated sympathetic nerve activity in the PVN of prehypertensive rats. CONCLUSIONS: Salt-induced prehypertension is partly due to the upregulation of TLR4 in PVN. Blockade of TLR4 in the brain reduced salt-induced prehypertension response, possibly through downregulation of ROS and PICs expression, and the restorage of neurotransmitter balance in the PVN.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Arterial/efeitos dos fármacos , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Pré-Hipertensão/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Rim/inervação , Masculino , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Pré-Hipertensão/metabolismo , Pré-Hipertensão/fisiopatologia , Ratos Sprague-Dawley , Cloreto de Sódio na Dieta , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Receptor 4 Toll-Like/metabolismo
19.
Asian J Androl ; 20(4): 355-359, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29516873

RESUMO

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.


Assuntos
Ejaculação/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Copulação , Feminino , Masculino , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Comportamento Sexual Animal/fisiologia , Nervos Esplâncnicos/citologia , Nervos Esplâncnicos/fisiologia
20.
Plant Physiol ; 176(4): 3103-3119, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29483147

RESUMO

Salicylic acid (SA) plays a crucial role in plant innate immunity. The deployment of SA-associated immune responses is primarily affected by SA concentration, which is determined by a balance between SA biosynthesis and catabolism. However, the mechanisms regulating SA homeostasis are poorly understood. In this study, we characterized a unique UDP-glycosyltransferase, UGT76D1, which plays an important role in SA homeostasis and associated immune responses in Arabidopsis (Arabidopsis thaliana). Expression of UGT76D1 was induced by treatment with both the pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 and SA. Overexpression of UGT76D1 resulted in high SA accumulation, significant up-regulation of pathogen-related genes, and a hypersensitive response (HR)-like lesion mimic phenotype. This HR-like phenotype was not observed following UGT76D1 overexpression in SA-deficient NahG transgenic or sid2 plants, suggesting that the phenotype is SA dependent. Biochemical assays showed that UGT76D1 glycosylated 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-dihydroxybenzoic acid (2,5-DHBA), the major catabolic forms of SA, to their Glc and Xyl conjugates in vitro and in vivo. Moreover, in a mutant background blocked in the formation of 2,3-DHBA and 2,5-DHBA, UGT76D1 overexpression did not cause a HR-like lesion mimic phenotype. Following infection with Pst DC3000, UGT76D1 knockout mutants displayed a delayed immune response, with reduced levels of DHBA glycosides and SA, and down-regulated SA synthase expression. By contrast, UGT76D1 overexpression lines showed an enhanced immune response and increased SA biosynthesis before and after pathogen infection. Thus, we propose that UGT76D1 plays an important role in SA homeostasis and plant immune responses by facilitating glycosylation of dihydroxybenzoic acids.


Assuntos
Arabidopsis/metabolismo , Gentisatos/metabolismo , Hidroxibenzoatos/metabolismo , Ácido Salicílico/metabolismo , Arabidopsis/genética , Arabidopsis/microbiologia , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Glicosilação , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Homeostase , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Plantas Geneticamente Modificadas , Pseudomonas syringae/fisiologia , Ácido Salicílico/farmacologia
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