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1.
Nat Commun ; 11(1): 4222, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839436

RESUMO

Our understanding of Na+ homeostasis has recently been reshaped by the notion of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na+ could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na+ in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na+ excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na+ excess, are both mechanistic and clinical.


Assuntos
Edema/metabolismo , Homeostase/fisiologia , Sódio/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia , Envelhecimento/metabolismo , Animais , Edema/diagnóstico , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Miocárdio/metabolismo , Especificidade de Órgãos , Concentração Osmolar , Potássio/metabolismo , Ratos Endogâmicos WKY , Pele/metabolismo , Fatores de Transcrição/metabolismo
2.
Life Sci ; 258: 118106, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682916

RESUMO

AIMS: Endothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. MAIN METHODS: The Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. KEY FINDINGS: Quercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SIGNIFICANCE: Quercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.


Assuntos
Autofagia/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Quercetina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
3.
J Oral Sci ; 62(3): 314-317, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581178

RESUMO

Administration of local anesthetics with adrenaline can cause tachycardia and hypertension. This study assessed whether combined administration of landiolol with adrenaline and lidocaine would induce local anesthesia without causing hemodynamic changes. Normal saline (NS), lidocaine with adrenaline (LA), and lidocaine with adrenaline and landiolol (LLA) were injected into Wistar Kyoto (WKY/Izm) or spontaneously hypertensive (SHR/Izm) rats, followed by measurement of the pulse rate (PR), and the systolic, diastolic and mean blood pressures (SBP, DBP and MBP). In the LLA group, the increase in PR was significantly suppressed in both SHR/Izm and WKY/Izm rats relative to those in the LA group. Although SBP was significantly reduced in WKY/Izm rats given LLA, relative to those given NS or LA, it was elevated in SHR/Izm rats given LLA. Landiolol-induced changes in PR may be due to blockade of adrenaline-induced ß1 receptor stimulation, which suppresses cardiac hyperactivity, whereas the early surge of blood pressure in SHR/Izm rats given LLA may be due to the dominant alpha-adrenergic effects of ß1 receptor inhibition. The anti-adrenergic effects of LLA were safe and effective in WKY/Izm rats, although the unexpected early hypertensive surge in SHR/Izm rats indicates the need for caution.


Assuntos
Epinefrina , Lidocaína , Animais , Morfolinas , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ureia/análogos & derivados
4.
Clin Exp Hypertens ; 42(8): 748-752, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32564622

RESUMO

OBJECTIVE: This study aimed to explore the mechanism of hypertensive brain damage from ferroptosis pathway. METHODS: Ten 22-week-old SHR rats were labeled as hypertension group(HBP), while ten WKY rats of comparable age, weight were used as normal blood pressure group(NBP). After 2 weeks of feeding, hypertensive brain damage was observed by comparing the pathological changes of brain tissue in SHR rats and WKY rats. Furthermore, the expression of GPX4 in the cerebral cortex was detected by immunofluorescence. The content of GSH was determined by spectrophotometer. The content of iron was detected by ferrous chromite colorimetry. And the content of MDA was determined by spectrophotometer. Compare the difference to investigate the role of ferroptosis mechanism in hypertensive brain damage. RESULTS: Brain damage occurred in 24-week-old SHR rats compared with WKY rats. In the HBP, the GPX4 and GSH were significantly lower than those in the NBP, and the total iron content and MDA were significantly increased. CONCLUSION: Thses findings suggest ferroptosis is closely related to hypertensive brain damage. Elevated blood pressure leads to iron overload in the brain. Excessive iron increases oxidative stress and lipid peroxidation in the brain, and eventually causes brain damage.


Assuntos
Encéfalo/patologia , Ferroptose , Hipertensão/patologia , Animais , Pressão Sanguínea , Encéfalo/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Peroxidação de Lipídeos , Masculino , Estresse Oxidativo/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
5.
PLoS One ; 15(6): e0233967, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497067

RESUMO

Radiation-induced heart disease presents a significant challenge in the event of an accidental radiation exposure as well as to cancer patients who receive acute doses of irradiation as part of radiation therapy. We utilized the spontaneously hypertensive Wistar-Kyoto rat model, previously shown to demonstrate drug-induced cardiomyopathy, to evaluate the acute and long-term effects of sub-lethal total body gamma irradiation at two, four, and fifty-two weeks. We further examined irreversible oxidative protein carbonylation in the heart immediately following irradiation in the normotensive Wistar-Kyoto rat. Both males and females sustained weight loss and anemic conditions compared to untreated controls over a one-year period as reflected by reduced body weight and low red blood cell count. Increased inflammation was detected by elevated IL-6 serum levels selectively in males at four weeks. Serum cardiac troponin T and I analyses revealed signs of cardiomyopathy at earlier timepoints, but high variability was observed, especially at one year. Echocardiography at two weeks following 5.0Gy treatment revealed a significant decrease in cardiac output in females and a significant decrease in both diastolic and systolic volumes in males. Following 10.0Gy irradiation in the normotensive Wistar-Kyoto rat, the heart tissue showed an increase in total protein oxidative carbonylation accompanied by DNA damage indicated by an increase in γ-H2AX. Using proteomic analyses, we identified several novel proteins which showed a marked difference in carbonylation including those of mitochondrial origin and most notably, cardiac troponin T, one of the key proteins involved in cardiomyocyte contractility. Overall, we present findings of acute oxidative protein damage, DNA damage, cardiac troponin T carbonylation, and long-term cardiomyopathy in the irradiated animals.


Assuntos
Raios gama/efeitos adversos , Coração/efeitos da radiação , Oxirredução/efeitos da radiação , Carbonilação Proteica/efeitos da radiação , Proteínas/química , Animais , Feminino , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Irradiação Corporal Total/efeitos adversos
6.
Clin Sci (Lond) ; 134(12): 1475-1489, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32538435

RESUMO

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1ß in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Cloridrato de Fingolimode/uso terapêutico , Peroxidase/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Animais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Anticorpos/imunologia , Apoptose , Feminino , Cloridrato de Fingolimode/farmacologia , Hematúria/complicações , Humanos , Células Jurkat , Rim/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proteinúria/complicações , Ratos Endogâmicos WKY , Transdução de Sinais
7.
PLoS One ; 15(5): e0233788, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470081

RESUMO

In pre-hypertension, moderate control of blood pressure (BP) can be obtained by a nutritional approach. The effects of a diet enriched with defatted larvae of the mealworm Tenebrio molitor (Coleoptera: Tenebrionidae) (TM) endowed with ACE inhibitory activity was studied in both spontaneously hypertensive rats (SHR) and in the age-matched normotensive Wistar Kyoto strain. These were fed for 4 weeks with standard laboratory rodent chow supplemented with or without TM or captopril. In SHR, the TM diet caused a significant reduction in BP, heart rate and coronary perfusion pressure, as well as an increase in red blood cell glutathione/glutathione disulphide ratio. Rat brain slices of SHR were more resistant to oxidative stress and contained lower levels of inflammatory cytokines, while vascular and liver enzyme-activities were not affected. These results suggest that TM can be considered a new functional food that can lower BP in vivo and thus control cardiovascular-associated risk factors such as hypertension.


Assuntos
Pressão Sanguínea , Suplementos Nutricionais , Frequência Cardíaca , Hipertensão/dietoterapia , Animais , Anti-Hipertensivos/farmacologia , Captopril/farmacologia , Hipertensão/tratamento farmacológico , Larva , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Tenebrio
8.
Artigo em Inglês | MEDLINE | ID: mdl-32357112

RESUMO

Plasticity is a fundamental property of neurons in both the central and peripheral nervous systems, enabling rapid changes in neural network function. The intracardiac nervous system (ICNS) is an extensive network of neurons clustered into ganglionated plexi (GP) on the surface of the heart. GP neurons are the final site of neuronal control of heart rhythm, and pathophysiological remodeling of the ICNS is proposed to feature in multiple cardiovascular diseases, including heart failure and atrial fibrillation. To examine the potential role of GP neuron plasticity in atrial arrhythmia and hypertension, we developed whole cell patch clamp recording techniques from GP neurons in isolated ICNS preparations from aged control (Wistar-Kyoto) and spontaneously hypertensive rats (SHRs). Anesthetized SHRs showed frequent premature ventricular contractions and episodes of atrial arrhythmia following carbachol injection, and isolated SHR atrial preparations were susceptible to pacing induced atrial arrhythmia. Whole cell recordings revealed elevated spontaneous postsynaptic current frequency in SHR GP neurons, as well as remodeled electrophysiology, with significant decreases in action potential amplitude and half-width. SHRs also showed a parallel increase in the number of cholinergic neurons and adrenergic glomus cells in cardiac ganglia, a higher proportion of synaptic α7-subunit but not ß2-containing nicotinic receptors, and an elevation in the number of synaptic terminals onto GP neurons. Our data show that significant structural and functional plasticity occurs in the intracardiac nervous system and suggest that enhanced excitability through synaptic plasticity, together with remodeling of cardiac neuron electrophysiology, contributes to the substrate for atrial arrhythmia in hypertensive heart disease.NEW & NOTEWORTHY We have developed intracardiac neuron whole cell recording techniques in atrial preparations from control and spontaneous hypertensive rats. This has enabled the identification of significant synaptic plasticity in the intracardiac nervous system, including enhanced postsynaptic current frequency, increased synaptic terminal density, and altered postsynaptic receptors. This increased synaptic drive together with altered cardiac neuron electrophysiology could increase intracardiac nervous system excitability and contribute to the substrate for atrial arrhythmia in hypertensive heart disease.


Assuntos
Arritmias Cardíacas/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Coração/inervação , Hipertensão/fisiopatologia , Plasticidade Neuronal/fisiologia , Potenciais de Ação , Animais , Átrios do Coração/fisiopatologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
9.
Life Sci ; 251: 117587, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32224027

RESUMO

Diabetes mellitus (DM) is a serious public health problem and can cause long-term damage to the brain, resulting in cognitive impairment in these patients. Insulin therapy for type 1 DM (DM1) can achieve overall blood glucose control, but glycemic variations can occur during injection intervals, which may contribute to some complications. Among the additional therapies available for DM1 treatment is the implantation of insulin-producing cells (IPCs) to attenuate hyperglycemia and even reverse diabetes. Here, we studied the strategy of implanting IPCs obtained from mesenchymal stromal cells (MSCs) from adipose tissue, comparing two different IPC implant sites, subcapsular renal (SR) and subcutaneous (SC), to investigate their putative protection against hippocampal damage, induced by STZ, in a rat DM1 model. Both implants improved hyperglycemia and reduced the serum content of advanced-glycated end products in diabetic rats, but serum insulin was not observed in the SC group. The SC-implanted group demonstrated ameliorated cognitive impairment (evaluated by novel object recognition) and modulation of hippocampal astroglial reactivity (evaluated by S100B and GFAP). Using GFP+ cell implants, the survival of cells at the implant sites was confirmed, as well as their migration to the pancreas and hippocampus. The presence of undifferentiated MSCs in our IPC preparation may explain the peripheral reduction in AGEs and subsequent cognitive impairment recovery, mediated by autophagic depuration and immunomodulation at the hippocampus, respectively. Together, these data reinforce the importance of MSCs for use in neuroprotective strategies, and highlight the logistic importance of the subcutaneous route for their administration.


Assuntos
Disfunção Cognitiva/prevenção & controle , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Insulina/metabolismo , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/citologia , Animais , Glicemia/metabolismo , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Produtos Finais de Glicação Avançada/sangue , Hipocampo/metabolismo , Hiperglicemia/terapia , Insulina/sangue , Masculino , Pâncreas/metabolismo , Ratos , Ratos Endogâmicos WKY
10.
PLoS One ; 15(4): e0231844, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315363

RESUMO

The vascular organ of the lamina terminalis, subfornical organ (SFO), and area postrema comprise the sensory circumventricular organs (CVO) which are central structures that lie outside the blood brain barrier and are thought to provide an interface between peripherally circulating signals and the brain through their projections to central autonomic structures. The SFO expresses mRNA for the G protein-coupled apelin receptor (APJ, gene name aplnr) and exogenous microinjection of the neuropeptide apelin (apln) to the SFO elicits a depressor effect. Here we investigated the expression and cellular distribution of aplnr, apln and the recently described ligand apela (apela) in the CVOs and investigated whether differences in the levels of expression of apelinergic gene transcripts in these regions might underlie the chronic elevated blood pressure seen in hypertension. We carried out multiplex in situ hybridization histochemistry on CVO tissue sections from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) controls. Confocal immunofluorescent images indicated strong aplnr expression, with lower levels of apln and modest apela expression, in the CVOs of both WKY rats and SHRs, in both neurons and glia. The expression level of aplnr transcripts was increased in the SFO of SHRs compared to WKY rats. Our data may highlight a potential dysfunction in the communication between CVOs and downstream signalling pathways in SHRs, which may contribute to its different phenotype/s.


Assuntos
Receptores de Apelina/metabolismo , Órgão Subfornical/metabolismo , Animais , Apelina/metabolismo , Hipertensão/metabolismo , Hipertensão/patologia , Hibridização in Situ Fluorescente , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Órgão Subfornical/patologia , Regulação para Cima
11.
PLoS One ; 15(4): e0231472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298299

RESUMO

Oxidative stress is involved in the pathogenesis of a number of diseases including hypertension and renal failure. There is enhanced expression of nicotinamide adenine dinucleotide (NADPH oxidase) and therefore production of hydrogen peroxide (H2O2) during renal disease progression. This study investigated the effect of apocynin, an NADPH oxidase inhibitor and catalase, an H2O2 scavenger on Cyclosporine A (CsA) nephrotoxicity in Wistar-Kyoto rats. Rats received CsA (25mg/kg/day via gavage) and were assigned to vehicle, apocynin (2.5mmol/L p.o.), catalase (10,000U/kg/day i.p.) or apocynin plus catalase for 14 days. Renal functional and hemodynamic parameters were measured every week, and kidneys were harvested at the end of the study for histological and NADPH oxidase 4 (NOX4) assessment. Oxidative stress markers and blood urea nitrogen (BUN) were measured. CsA rats had higher plasma malondialdehyde (by 340%) and BUN (by 125%), but lower superoxide dismutase and total antioxidant capacity (by 40%, all P<0.05) compared to control. CsA increased blood pressure (by 46mmHg) and decreased creatinine clearance (by 49%, all P<0.05). Treatment of CsA rats with apocynin, catalase, and their combination decreased blood pressure to near control values (all P<0.05). NOX4 mRNA activity was higher in the renal tissue of CsA rats by approximately 63% (P<0.05) compared to controls but was reduced in apocynin (by 64%), catalase (by 33%) and combined treatment with apocynin and catalase (by 84%) compared to untreated CsA rats. Treatment of CsA rats with apocynin, catalase, and their combination prevented hypertension and restored renal functional parameters and tissue Nox4 expression in this model. NADPH inhibition and H2O2 scavenging is an important therapeutic strategy during CsA nephrotoxicity and hypertension.


Assuntos
Acetofenonas/farmacocinética , Lesão Renal Aguda/induzido quimicamente , Catalase/farmacologia , Ciclosporina/toxicidade , Hipertensão/induzido quimicamente , Lesão Renal Aguda/prevenção & controle , Animais , Hemodinâmica/efeitos dos fármacos , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , NADPH Oxidase 4/metabolismo , Reação em Cadeia da Polimerase , Ratos , Ratos Endogâmicos WKY
12.
Mol Pharmacol ; 97(6): 365-376, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32234808

RESUMO

Proteinase-activated receptors (PARs) are a four-member family of G-protein-coupled receptors that are activated via proteolysis. PAR4 is a member of this family that is cleaved and activated by serine proteinases such as thrombin, trypsin, and cathepsin-G. PAR4 is expressed in a variety of tissues and cell types, including platelets, vascular smooth muscle cells, and neuronal cells. In studying PAR4 signaling and trafficking, we observed dynamic changes in the cell membrane, with spherical membrane protrusions that resemble plasma membrane blebbing. Since nonapoptotic membrane blebbing is now recognized as an important regulator of cell migration, cancer cell invasion, and vesicular content release, we sought to elucidate the signaling pathway downstream of PAR4 activation that leads to such events. Using a combination of pharmacological inhibition and CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing approaches, we establish that PAR4-dependent membrane blebbing occurs independently of the Gα q/11- and Gα i-signaling pathways and is dependent on signaling via the ß-arrestin-1/2 and Ras homolog family member A (RhoA) signaling pathways. Together these studies provide further mechanistic insight into PAR4 regulation of cellular function. SIGNIFICANCE STATEMENT: We find that the thrombin receptor PAR4 triggers cell membrane blebbing in a RhoA-and ß-arrestin-dependent manner. In addition to identifying novel cellular responses mediated by PAR4, these data provide further evidence for biased signaling in PAR4 since membrane blebbing was dependent on some, but not all, signaling pathways activated by PAR4.


Assuntos
Membrana Celular/metabolismo , Membrana Celular/patologia , Receptores de Trombina/metabolismo , beta-Arrestinas/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Sistemas CRISPR-Cas , Forma Celular , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Músculo Liso Vascular/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Trombina/agonistas , Transdução de Sinais
13.
Toxicol Appl Pharmacol ; 394: 114950, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147540

RESUMO

The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of vitamin D, improves autonomic and cardiovascular function in hypertensive rats and whether PVN oxidative stress and inflammation are involved in these beneficial effects. Male spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were treated with either calcitriol (40 ng/day) or vehicle (0.11 µL/h) through chronic PVN infusion for 4 weeks. Blood pressure and heart rate were recorded continuously by radiotelemetry. PVN tissue, heart and plasma were collected for molecular and histological analysis. Compared to WKY rats, SHR exhibited increased systolic blood pressure, sympathetic drive, and cardiac hypertrophy and remodeling. These were associated with higher mRNA and protein expression levels of high mobility box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), proinflammatory cytokines, NADPH oxidase subunit in the PVN. In addition, increased norepinephrine in plasma, elevated reactive oxygen species levels and activation of microglia in the PVN were also observed in SHR. Chronic calcitriol treatment ameliorated these changes but not in WKY rats. Our results demonstrate that chronic infusion of calcitriol in the PVN ameliorates hypertensive responses, sympathoexcitation and retains cardiovascular function in SHR. Reduced inflammation and oxidative stress within the PVN are involved in these calcitriol-induced effects.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Calcitriol/uso terapêutico , Agonistas dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Doenças do Sistema Nervoso Autônomo/genética , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/genética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
14.
Toxicol Appl Pharmacol ; 394: 114953, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32165127

RESUMO

Exercise training is one of the major non-pharmacological treatments for hypertension. However, the central mechanism by which exercise training attenuates the hypertensive responses remains unclear. Irisin is a muscle-secreted cytokine derived from fibronectin type III domain containing 5 (FNDC5) that will be released into the circulation during exercise. We hypothesized that irisin may play a role in the blood pressure regulation by exercise. To examine the hypothesis, our study investigated the effect of irisin on hypertension and its central mechanism. The study was performed in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats. We found that intravenous injection of irisin effectively reduced blood pressure, plasma norepinephrine, paraventricular nucleus (PVN) levels of neuronal activation, oxidative stress and inflammation in SHRs. Moreover, irisin activated nuclear factor E2-related factor-2 (Nrf2) and restored the imbalance of neurotransmitters in the PVN. Our study also found PVN knockdown of Nrf2 abolished the protective effects of irisin on hypertension. These findings demonstrate irisin can improve hypertension via Nrf2-mediated antioxidant in the PVN.


Assuntos
Anti-Hipertensivos/farmacologia , Fibronectinas/farmacologia , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Citocinas/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/sangue , Estresse Oxidativo/efeitos dos fármacos , Esforço Físico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
15.
Int J Nanomedicine ; 15: 729-734, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32099361

RESUMO

Background: Recently, use of nanotechnology in biomedical applications such as drug delivery and diagnostic and therapeutic tools has increased greatly. This study evaluated gold nanoparticle (GNPs)-induced nephrotoxic effects in rats in vivo, and examined protective effects of alpha-lipoic acid (α-Lip) and Vitamin E (Vit E) against nephrotoxicity, lipid peroxidation, and inflammatory kidney damage induced by GNPs. Materials and Methods: Twenty-four male Wistar-Kyoto rats (220-240 g, 12 weeks old) were dosed with 50 µL of 10 nm GNPs administered intraperitoneally with or without 200 mg/kg/day Vit E or 200 mg/kg/day α-Lip. Serum was prepared for biochemical analyses. Kidney function was evaluated through measurement of creatinine (CR), uric acid (URIC), and blood urea nitrogen (BUN). Oxidative stress and lipid peroxidation were evaluated by measurement of reduced glutathione (GSH) and malondialdehyde (MDA) in kidney tissue homogenates. Results and Conclusions: The results showed a significant rise in serum kidney function biomarkers including urea, URIC, CR, and BUN in GNP-treated rats compared to normal control rats. Furthermore, GNPs led to decreased GSH and elevated MDA levels. Vit E or α-Lip supplementation showed a beneficial effect against nephrotoxicity, lipid peroxidation, and inflammatory kidney damage induced by GNPs. This study suggests that use of natural antioxidants in combination with GNPs may be a useful tool in preventing GNPs toxicity.


Assuntos
Ouro/toxicidade , Inflamação/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Ácido Tióctico/farmacologia , Vitamina E/farmacologia , Animais , Biomarcadores/metabolismo , Creatinina/sangue , Glutationa/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Endogâmicos WKY , Ácido Úrico/sangue
16.
Gene ; 737: 144479, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32068124

RESUMO

BACKGROUND: Cardiac and renal dysfunction are often co-morbid pathologies leading to worsening prognosis resulting in difficulty in therapy of left ventricular hypertrophy (LVH). The aim of the current study was to determine the changes in expression of human ortholog genes of hypertension, vascular and cardiac remodeling and hypertensive nephropathy phenotypes under normal, disease and upon treatment with gasotransmitter including H2S (hydrogen sulphide), NO (nitric oxide) and combined (H2S + NO). METHODS: A total of 72 Wistar Kyoto rats (with equivalent male and female animals) were recruited in the present study where LVH rat models were treated with H2S and NO individually as well as with both combined. Cardiac and renal physical indices were recorded and relative gene expression were quantified. RESULTS: Both cardiac and renal physical indices were significantly modified with individual as well as combined H2S + NO treatment in control and LVH rats. Expression analysis revealed, hypertension, vascular remodeling genes ACE, TNFα and IGF1, mRNAs to be significantly higher (P ≤ 0.05) in the myocardia and renal tissues of LVH rats, while individual and combined H2S + NO treatment resulted in lowering the gene expression to normal/near to normal levels. The cardiac remodeling genes MYH7, TGFß, SMAD4 and BRG1 expression were significantly up-regulated (P ≤ 0.05) in the myocardia of LVH where the combined H2S + NO treatment resulted in normal/near to normal expression more effectively as compared to individual treatments. In addition individual as well as combined H2S and NO treatment significantly decreased PKD1 expression in renal tissue, which was up-regulated in LVH rats (P ≤ 0.05). CONCLUSIONS: The reduction in hemodynamic parameters and cardiac indices as well as alteration in gene expression on treatment of LVH rat model indicates important therapeutic potential of combined treatment with H2S + NO gasotransmitters in hypertension and cardiac hypertrophy when present as co-morbidity with renal complications.


Assuntos
Expressão Gênica/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Hipertensão Renal/genética , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Nefrite/genética , Óxido Nítrico/farmacologia , Remodelação Vascular/genética , Remodelação Ventricular/genética , Animais , Progressão da Doença , Feminino , Humanos , Sulfeto de Hidrogênio/sangue , Masculino , Óxido Nítrico/sangue , Ratos , Ratos Endogâmicos WKY , Canais de Cátion TRPP/genética
17.
Clin Chem ; 66(2): 333-341, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040581

RESUMO

BACKGROUND: Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). METHODS: We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. RESULTS: Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. CONCLUSION: Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.


Assuntos
Infarto do Miocárdio/metabolismo , Troponina I/metabolismo , Troponina T/metabolismo , Animais , Biomarcadores/sangue , Insuficiência Cardíaca/sangue , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos WKY , Sarcômeros/metabolismo , Troponina I/sangue , Troponina T/sangue
18.
J Pharmacol Exp Ther ; 373(1): 135-148, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32015161

RESUMO

By reducing their metabolism, dipeptidyl peptidase 4 inhibition (DPP4I) enhances the effects of numerous peptides including neuropeptide Y1-36 (NPY1-36), peptide YY1-36 (PYY1-36), and SDF-1α Studies show that separately NPY1-36, PYY1-36 and SDF-1α stimulate proliferation of, and collagen production by, cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs), particularly in cells isolated from genetically hypertensive rats. Whether certain combinations of these factors, in the absence or presence of DPP4I, are more profibrotic than others is unknown. Here we contrasted 24 different combinations of conditions (DPP4I, hypertensive genotype and physiologic levels [3 nM] of NPY1-36, PYY1-36, or SDF-1α) on proliferation of, and [3H]-proline incorporation by, CFs, PGVSMCs, and GMCs. In all three cell types, the various treatment conditions differentially increased proliferation and [3H]-proline incorporation, with a hypertensive genotype + DPP4I + NPY1-36 + SDF-1α being the most efficacious combination. Although the effects of this four-way combination were similar in male versus female CFs, physiologic (1 nM) concentrations of 2-methoxyestradiol (2ME; nonestrogenic metabolite of 17ß-estradiol), abolished the effects of this combination in both male and female CFs. In conclusion, this study demonstrates that CFs, PGVSMCs, and GMCs are differentially activated by various combinations of NPY1-36, PYY1-36, SDF-1α, a hypertensive genetic background and DPP4I. We hypothesize that as these progrowth conditions accumulate, a tipping point would be reached that manifests in the long term as organ fibrosis and that 2ME would obviate any profibrotic effects of DPP4I, even under the most profibrotic conditions (i.e., hypertensive genotype with high NPY1-36 + SDF-1α levels and low 2ME levels). SIGNIFICANCE STATEMENT: This work elucidates combinations of factors that could contribute to long-term profibrotic effects of dipeptidyl peptidase 4 inhibitors and suggests a novel drug combination that could prevent any potential profibrotic effects of dipeptidyl peptidase 4 inhibitors while augmenting the protective effects of this class of antidiabetic agents.


Assuntos
2-Metoxiestradiol/farmacologia , Quimiocina CXCL12/sangue , Colágeno/biossíntese , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipertensão/sangue , Neuropeptídeo Y/sangue , Fragmentos de Peptídeos/sangue , 2-Metoxiestradiol/uso terapêutico , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Hipertensão/genética , Hipertensão/patologia , Masculino , Peptídeo YY/sangue , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
19.
J Pharmacol Exp Ther ; 373(2): 175-183, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32071104

RESUMO

Decreased release of palmitic acid methyl ester (PAME), a vasodilator, from perivascular adipose tissue (PVAT) might contribute to hypertension pathogenesis. However, the PAME biosynthetic pathway remains unclear. In this study, we hypothesized that PAME is biosynthesized from palmitic acid (PA) via human catechol-O-methyltransferase (COMT) catalysis and that decreased PAME biosynthesis plays a role in hypertension pathogenesis. We compared PAME biosynthesis between age-matched normotensive Wistar Kyoto (WKY) rats and hypertensive spontaneously hypertensive rats (SHRs) and investigated the effects of losartan treatment on PAME biosynthesis. Computational molecular modeling indicated that PA binds well at the active site of COMT. Furthermore, in in vitro enzymatic assays in the presence of COMT and S-5'-adenosyl-L-methionine (AdoMet), the stable isotope [13C16]-PA was methylated to form [13C16]-PAME in incubation medium or the Krebs-Henseleit solution containing 3T3-L1 adipocytes or rat PVAT. The adipocytes and PVATs expressed membrane-bound (MB)-COMT and soluble (S)-COMT proteins. [13C16]-PA methylation to form [13C16]-PAME in 3T3-L1 adipocytes and rat PVAT was blocked by various COMT inhibitors, such as S-(5'-adenosyl)-L-homocysteine, adenosine-2',3'-dialdehyde, and tolcapone. MB- and S-COMT levels in PVATs of established SHRs were significantly lower than those in PVATs of age-matched normotensive WKY rats, with decreased [13C16]-PA methylation to form [13C16]-PAME. This decrease was reversed by losartan, an angiotensin II (Ang II) type 1 receptor antagonist. Therefore, PAME biosynthesis in rat PVAT is dependent on AdoMet, catalyzed by COMT, and decreased in SHRs, further supporting the role of PVAT/PAME in hypertension pathogenesis. Moreover, the antihypertensive effect of losartan might be due partly to its increased PAME biosynthesis. SIGNIFICANCE STATEMENT: PAME is a key PVAT-derived relaxing factor. We for the first time demonstrate that PAME is synthesized through PA methylation via the S-5'-adenosyl-L-methionine-dependent COMT catalyzation pathway. Moreover, we confirmed PVAT dysfunction in the hypertensive state. COMT-dependent PAME biosynthesis is involved in Ang II receptor type 1-mediated blood pressure regulation, as evidenced by the reversal of decreased PAME biosynthesis in PVAT by losartan in hypertensive rats. This finding might help in developing novel therapeutic or preventive strategies against hypertension.


Assuntos
Tecido Adiposo/metabolismo , Catecol O-Metiltransferase/fisiologia , Hipertensão/tratamento farmacológico , Palmitatos/metabolismo , Células 3T3-L1 , Animais , Catálise , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Simulação por Computador , Losartan/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-Dawley
20.
Bratisl Lek Listy ; 121(1): 73-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31950843

RESUMO

AIM: The aim of the present study was to investigate the immunohistochemical expression of selected collagen types, namely collagen types I and V and procollagen type III in the renal parenchyma and interstitium and in the myocardium of spontaneously hypertensive rats. MATERIAL AND METHODS: For the present study, we used two age groups of 6- and 12-month-old spontaneously hypertensive rats. An immunohistochemical analysis was conducted with monoclonal antibodies against collagen types I and V and procollagen type III. A semi-quantitative analysis of immunostaining intensity was conducted with the Image J software. RESULTS: In the kidney, all three molecules showed higher expression at the age of 12 months, which was particularly notable for procollagen type III and collagen type V, which stained as highly-positive. In the myocardium, the immunoreactivity of collagen types I and V was stronger in 12-month-old animals, while that of procollagen type III did not change substantially. CONCLUSION: The present study suggests a role of collagen types III and V in hypertensive kidney disease, while also establishing the role of increased expression of collagen types I and V in adverse myocardial remodeling (Tab. 1, Fig. 2, Ref. 48).


Assuntos
Hipertensão , Rim , Miocárdio , Animais , Colágeno/metabolismo , Coração , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Remodelação Vascular
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