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1.
Am J Physiol Heart Circ Physiol ; 319(2): H341-H348, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618512

RESUMO

Progesterone exerts antihypertensive actions partially by modulating endothelial nitric oxide synthase (eNOS) activity. Here, we aimed to investigate the effects and mechanisms of progesterone on eNOS expression. First, human umbilical vein endothelial cells (HUVECs) were exposed to progesterone and then the eNOS transcription factor specificity protein-1 (SP-1) and progesterone receptor (PRA/B) expression were assessed by Western blotting and qRT-PCR. The interaction between SP-1 and PRA/B was next determined through coimmunoprecipitation assay. The chromatin immunoprecipitation assay and luciferase assay were used to investigate the relationship of PRA/B, SP-1, and eNOS promoter. At last, rats were intraperitoneally injected with progesterone receptor antagonist RU-486, and then the expression of eNOS and vasodilation function in thoracic aorta and mesenteric artery were measured. The results showed that progesterone could increase eNOS expression in HUVECs. Further study showed that progesterone increased PRA-SP-1 complex formation and facilitated PRA/B and SP-1 binding to eNOS promoter. Mutating SP-1 or PR-binding motif on eNOS promoter abolished the effect of progesterone on eNOS gene transcription. We also observed that progesterone receptor antagonist RU-486 reduced eNOS expression and impaired vasodilation in rats. Those results suggest that progesterone modulates eNOS expression through promoting PRA-SP-1 complex formation, and progesterone antagonist attenuates eNOS expression, leading to the loss of vascular relaxation.NEW & NOTEWORTHY Progesterone directly upregulated endothelial nitric oxide synthase (eNOS) expression in human endothelial cells. Progesterone augmented eNOS promoter activity through a progesterone receptor A- and specificity protein-1-dependent manner. Antagonism of the progesterone receptor reduced eNOS expression and impaired vasodilation in rats.


Assuntos
Núcleo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/biossíntese , Progesterona/farmacologia , Receptores de Progesterona/agonistas , Fator de Transcrição Sp1/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Sítios de Ligação , Núcleo Celular/metabolismo , Células Cultivadas , Indução Enzimática , Feminino , Antagonistas de Hormônios/farmacologia , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Óxido Nítrico Sintase Tipo III/genética , Regiões Promotoras Genéticas , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Transdução de Sinais , Vasodilatação/efeitos dos fármacos
2.
Life Sci ; 256: 117986, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585245

RESUMO

AIMS: HSP70, a molecular chaperone, helps to maintain proteostasis. In muscle biology, however, evidence suggests HSP70 to have a more versatile range of functions, as genetic deletion of its inducible genes impairs Ca2+ handling, and consequently, cardiac and skeletal muscle contractility. Still, it is unknown whether HSP70 is involved in vascular reactivity, an intrinsic physiological mechanism of blood vessels. Therefore, we designed this study to test the hypothesis that proper vascular reactivity requires the assistance of HSP70. MAIN METHODS: We performed functional studies in a wire-myograph using thoracic aorta isolated from male Sprague Dawley rats. Experiments were conducted with and without an HSP70 inhibitor as well as in heat-stressed vessels. The expression levels of HSP70 were evaluated with Western blotting. NO and ROS levels were assessed with fluorescence microscopy. KEY FINDINGS: We report that blockade of HSP70 weakens contraction in response to phenylephrine (dose-response) in the aorta. Additionally, we demonstrated that inhibition of HSP70 affects the amplitude of the fast and of the slow components of the time-force curve. Corroborating these findings, we found that inhibition of HSP70, in vessels over-expressing this protein, partly rescues the contractile phenotype of aortic rings. Furthermore, we show that blockade of HSP70 facilitates relaxation in response to acetylcholine and clonidine without affecting the basal levels of NO and ROS. SIGNIFICANCE: Our work introduces an additional physiological role for HSP70, the assistance of vascular reactivity, which highlights this protein as a new player in vascular physiology, and therefore, uncovers a promising research avenue for vascular diseases.


Assuntos
Aorta Torácica/fisiologia , Endotélio Vascular/fisiologia , Proteínas de Choque Térmico HSP70/fisiologia , Músculo Liso Vascular/fisiologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/agonistas , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Fenilefrina/farmacologia , Nucleosídeos de Purina/farmacologia , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
3.
Toxicol Appl Pharmacol ; 398: 115012, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320793

RESUMO

INTRODUCTION: Crotonaldehyde (CR) is an electrophilic α,ß-unsaturated aldehyde present in foods and beverages and is a minor metabolite of 1,3-butadiene. CR is a product of incomplete combustion, and is at high levels in smoke of cigarettes and structural fires. Exposure to CR has been linked to cardiopulmonary toxicity and cardiovascular disease. OBJECTIVE: The purpose of this study was to examine the direct effects of CR in murine blood vessels (aorta and superior mesenteric artery, SMA) using an in vitro system. METHODS AND RESULTS: CR induced concentration-dependent (1-300 µM) relaxations (75-80%) in phenylephrine (PE) precontracted aorta and SMA. Because the SMA was 20× more sensitive to CR than aorta (SMA EC50 3.8 ± 0.5 µM; aorta EC50 76.0 ± 2.0 µM), mechanisms of CR relaxation were studied in SMA. The CR-induced relaxation at low concentrations (1-30 µM) was inhibited by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); 4) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); and, 5) by non-vasoactive level of nicotine (1 µM). Similarly, a TRPA1 agonist, allyl isothiocyanate (AITC; mustard oil), stimulated SMA relaxation dependent on TRPA1, endothelium, NO, and GC. Consistent with these mechanisms, TRPA1 was present in the SMA endothelium. CR, at higher concentrations (100-300 µM), induced tension oscillations (spasms) and irreversibly impaired contractility (a vasotoxic effect enhanced by impaired endothelium). CONCLUSIONS: CR relaxation depends on a functional endothelium and TRPA1, whereas vasotoxicity is enhanced by endothelium dysfunction. Thus, CR is both vasoactive and vasotoxic along a concentration continuum.


Assuntos
Aldeídos/farmacologia , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Canal de Cátion TRPA1/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Endotélio Vascular/metabolismo , Feminino , Masculino , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Fenilefrina/metabolismo
4.
J Vasc Res ; 57(4): 213-222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294645

RESUMO

INTRODUCTION: Although both glucose and fructose are hexoses, their catabolism is quite different: the catabolism of fructose is initiated by ketohexokinase and is not regulated by negative feedback, which results in oxidative stress. OBJECTIVE: We hypothesized that fructose impairs endothelium-dependent relaxation via oxidative stress in rat aortic rings. METHODS: Sprague-Dawley rats were offered 20% fructose solution or tap water for 2 weeks, after which vascular reactivity was measured in isolated aortic rings. In a separate experiment, vascular reactivity was measured after acute exposure to ∼10 mM fructose in isolated aortic rings from untreated rats. RESULTS: Although high-fructose intake statistically significantly increased blood pressure and body weight, it did not affect contraction and relaxation in aortic rings. The substitution of fructose for glucose in Krebs solution inhibited vascular relaxation in aortic rings, which was abolished by pretreatment with antioxidants. Decreasing the glucose concentration in Krebs solution inhibited vascular relaxation, whereas decreasing the fructose concentration in Krebs solution improved vascular relaxation in the aortic rings. Pretreatment with antioxidants improved the vascular relaxation in Krebs solution with fructose substituted for glucose. CONCLUSIONS: These results indicate that fructose impairs endothelium-dependent relaxation via oxidative stress in isolated rat aortic rings.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Frutose/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Técnicas In Vitro , Masculino , Ratos Sprague-Dawley , Ganho de Peso/efeitos dos fármacos
5.
Biol Pharm Bull ; 43(3): 404-408, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115501

RESUMO

The aim of this study was to investigate the effects of egg yolk powder enriched with astaxanthin (ASX-E) on blood pressure in spontaneously hypertensive rats (SHR) and to verify the benefits of ASX-E as a functional food. To investigate the antihypertensive effect, SHR were fed with an ASX-E mixed diet before hypertension development. Blood pressures were determined periodically during the study by the tail-cuff method. At the end of the study, animals were euthanized, and their thoracic aortas were collected to determine vascular conductance. The thoracic aorta tension was measured with a force displacement transducer. Concentration-dependent response relationships were determined by cumulative addition of 10-9-10-4 M Carbamoylcholine (Cch). Blood pressures of the SHR in the ASX-E mixed diet group were ASX-dose-dependently lower than that of those in the control group. In SHR fed with an ASX-E mixed diet, Cch induced vasorelaxation in the thoracic aorta with endothelium lining but not without endothelium. However, the antihypertensive effect of ASX-E was not observed on blood pressures in SHR that were fed with ASX-E only after the development of hypertension. Results suggest that ASX-E protects endothelial function and thereby prevents the development of hypertension. Hence, the results of our research indicate that daily consumption of ASX-E has a potential benefit on human health.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Animais , Aorta Torácica/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Dieta , Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos SHR , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Xantofilas/farmacologia
6.
PLoS One ; 15(2): e0229435, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32107491

RESUMO

A collection of evidence suggests that conjugation of double bonds of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, omega-3 polyunsaturated fatty acids (n-3 PUFAs), increases their anticarcinogenic activity; however, the effect of such conjugation on vascular tone activity remains unknown. We propose that the mixture of conjugated PUFAs exerts higher vasorelaxation activity than the corresponding mixture of nonconjugated PUFAs. The vascular response to different concentrations of conjugated and nonconjugated isomers of EPA and DHA, among other fatty acids (FAs) naturally present in shark oil, and the role of nitric oxide (NO) as a vasorelaxant agent were investigated. Both conjugated EPA (CEPA) and conjugated DHA (CDHA) were prepared by alkaline isomerization of all PUFAs contained in shark oil. Different concentrations of conjugated and nonconjugated PUFAs were placed in contact with precontracted aortic rings of Wistar rats to assess their effect on vascular tone. All tested samples exerted a vasorelaxant effect. Compared to nonconjugated PUFAs, conjugated isomers exhibited an increase in the dilatation of the aortic rings (P<0.001) in a dose-dependent manner (P<0.001). In addition, nonconjugated PUFAs produced nitric oxide (NO) in a dose-dependent manner, while conjugated PUFAs did not, suggesting that their dilatation mechanism is not totally dependent on NO.


Assuntos
Aorta Torácica/fisiologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Óleos de Peixe/farmacologia , Óxido Nítrico/metabolismo , Vasodilatação/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ácidos Graxos/metabolismo , Óleos de Peixe/química , Isomerismo , Masculino , Ratos , Ratos Wistar , Tubarões , Vasodilatação/efeitos dos fármacos
7.
Life Sci ; 245: 117357, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31991180

RESUMO

AIMS: Schisandra is a good choice in Traditional Chinese Medicine for the therapy of cardiovascular diseases, but whether it contains a or some specific component (s) responsible these effects are still unclear. In the present study, we explored whether Schisantherin A (SCA) causes vasorelaxation in isolated rat thoracic aorta. MAIN METHODS: We selected SCA, one of the main monomers of lignans from Schisandra, to examine its vasorelaxant effect on the isolated rat thoracic aorta and also exploited several tool inhibitors to probe its underlying mechanisms. KEY FINDINGS: SCA produced relaxation concentration-dependently on the endothelium-intact (43.56 ± 2.17%) and endothelium-denuded thoracic aorta strips (18.76 ± 3.95%) pre-contracted by phenylephrine (PE). However, after treated with indomethacin or L-NAME, SCA showed only partial vasorelaxant effects. Whereas, this vasorelaxation by SCA was not changed with specific K+-channel inhibitors, i.e. barium chloride (BaCl2), 4-aminopyridine (4-AP), tetraethylamine (TEA), and glibenclamide. SCA had no effect on the aorta strips pre-contracted by PE in neither Ca2+-free nor CaCl2 conditions. But, in the Ca2+ free and high K+ environment, SCA partly abolished the vasocontraction induced by CaCl2. SIGNIFICANCE: It was the first report to demonstrate that SCA had endothelium-dependent and -independent vasorelaxant effects on the isolated rat thoracic aorta, and the underlying mechanisms might be involved into its promoting the production of nitric oxide (NO) and prostacyclin (PGI2), and inhibiting the voltage-dependent calcium channels (VDCCs) opening. This study may partially explain the use of Schisandra in cardiovascular diseases and facilitate further drug development as well.


Assuntos
Aorta Torácica/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Dioxóis/farmacologia , Endotélio Vascular/efeitos dos fármacos , Lignanas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Western Blotting , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Masculino , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Arterioscler Thromb Vasc Biol ; 40(3): 751-765, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31941382

RESUMO

OBJECTIVES: Vascular calcification is highly prevalent in patients with chronic kidney disease. Increased plasma trimethylamine N-oxide (TMAO), a gut microbiota-dependent product, concentrations are found in patients undergoing hemodialysis. However, a clear mechanistic link between TMAO and vascular calcification is not yet established. In this study, we investigate whether TMAO participates in the progression of vascular calcification using in vitro, ex vivo, and in vivo models. Approach and Results: Alizarin red staining revealed that TMAO promoted calcium/phosphate-induced calcification of rat and human vascular smooth muscle cells in a dose-dependent manner, and this was confirmed by calcium content assay. Similarly, TMAO upregulated the expression of bone-related molecules including Runx2 (Runt-related transcription factor 2) and BMP2 (bone morphogenetic protein-2), suggesting that TMAO promoted osteogenic differentiation of vascular smooth muscle cells. In addition, ex vivo study also showed the positive regulatory effect of TMAO on vascular calcification. Furthermore, we found that TMAO accelerated vascular calcification in rats with chronic kidney disease, as indicated by Mico-computed tomography analysis, alizarin red staining and calcium content assay. By contrast, reducing TMAO levels by antibiotics attenuated vascular calcification in chronic kidney disease rats. Interestingly, TMAO activated NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB (nuclear factor κB) signals during vascular calcification. Inhibition of NLRP3 inflammasome and NF-κB signals attenuated TMAO-induced vascular smooth muscle cell calcification. CONCLUSIONS: This study for the first time demonstrates that TMAO promotes vascular calcification through activation of NLRP3 inflammasome and NF-κB signals, suggesting the potential link between gut microbial metabolism and vascular calcification. Reducing the levels of TMAO could become a potential treatment strategy for vascular calcification in chronic kidney disease.


Assuntos
Inflamassomos/efeitos dos fármacos , Metilaminas/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteogênese/efeitos dos fármacos , Calcificação Vascular/induzido quimicamente , Adulto , Idoso , Animais , Antibacterianos/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos/metabolismo , Masculino , Metilaminas/metabolismo , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Artérias da Tíbia/efeitos dos fármacos , Artérias da Tíbia/metabolismo , Artérias da Tíbia/patologia , Técnicas de Cultura de Tecidos , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Calcificação Vascular/prevenção & controle
9.
Chem Biol Interact ; 316: 108923, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838051

RESUMO

Angina pectoris can be used as an early warning for coronary artery disease. Vasodilation is an important mechanism of angina pectoris. Traditional Chinese medicine - Compound Danshen Dripping Pill (CDDP) is widely used to improve the symptoms of cardiovascular diseases (CVDs). To investigate the influence of vasodilation effect and underlying mechanisms of CDDP, we determined the vasodilation effect of thoracic aorta ring on rat induced by norepinephrine (NE). Then targets-fishing method was used to predict the potential mechanism of CDDP on vasodilation, based on the structures of the main components. Then, iTRAQ-based quantitative proteomics analysis was used for verification of the candidate target proteins and pathways to illustrate the underlying mechanisms. Furthermore, the differentially expressed proteins in the enriched pathways were validated by western blotting. In this study, we found that CDDP could significantly inhibit NE induced aortic contraction tension, and the mechanism may be related to platelet activation, cGMP - PKG signaling pathway and vascular smooth muscle contraction. The method provides a new way to uncover the vasodilation mechanism of CDDP, as well as other multi-component herbal medicines.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Proteoma/análise , Proteômica , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Masculino , Medicina Tradicional Chinesa , Contração Muscular/efeitos dos fármacos , Norepinefrina/farmacologia , Proteoma/efeitos dos fármacos , Proteoma/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
10.
Chem Biol Interact ; 315: 108887, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31705857

RESUMO

AIM: To investigate the molecular, structural, and functional impact of aerosols from candidate modified risk tobacco products (cMRTP), the Carbon Heated Tobacco Product (CHTP) 1.2 and Tobacco Heating System (THS) 2.2, compared with that of mainstream cigarette smoke (CS) on the cardiovascular system of ApoE-/- mice. METHODS: Female ApoE-/- mice were exposed to aerosols from THS 2.2 and CHTP 1.2 or to CS from the 3R4F reference cigarette for up to 6 months at matching nicotine concentrations. A Cessation and a Switching group (3 months exposure to 3R4F CS followed by filtered air or CHTP 1.2 for 3 months) were included. Cardiovascular effects were investigated by echocardiographic, histopathological, immunohistochemical, and transcriptomics analyses. RESULTS: Continuous exposure to cMRTP aerosols did not affect atherosclerosis progression, heart function, left ventricular (LV) structure, or the cardiovascular transcriptome. Exposure to 3R4F CS triggered atherosclerosis progression, reduced systolic ejection fraction and fractional shortening, caused heart LV hypertrophy, and initiated significant dysregulation in the transcriptomes of the heart ventricle and thoracic aorta. Importantly, the structural, functional, and molecular changes caused by 3R4F CS were improved in the smoking cessation and switching groups. CONCLUSION: Exposure to cMRTP aerosols lacked most of the CS exposure-related functional, structural, and molecular effects. Smoking cessation or switching to CHTP 1.2 aerosol caused similar recovery from the 3R4F CS effects in the ApoE-/- model, with no further acceleration of plaque progression beyond the aging-related rate.


Assuntos
Aerossóis/efeitos adversos , Apolipoproteínas E/metabolismo , Carbono/efeitos adversos , Sistema Cardiovascular/efeitos dos fármacos , Fumaça/efeitos adversos , Produtos do Tabaco/efeitos adversos , Tabaco/efeitos adversos , Animais , Aorta Torácica/efeitos dos fármacos , Aterosclerose/metabolismo , Sistema Cardiovascular/metabolismo , Feminino , Calefação/efeitos adversos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Fumar/efeitos adversos , Transcriptoma/efeitos dos fármacos
11.
Eur J Vasc Endovasc Surg ; 59(6): 1000-1010, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31879145

RESUMO

OBJECTIVE: Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. METHODS: ß-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n = 30) (21%-5% O2, 90 s/cycle, 10 h/day, IH + BAPN group) or normoxia (n = 30) (21% O2, 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O2)/re-oxygenation (30 min, 21% O2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1α and LOX via HIF-1α-siRNA. RESULTS: It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1ß, IL-6, cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1α. CONCLUSION: The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice.


Assuntos
Aneurisma Dissecante/terapia , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/terapia , Hipóxia/fisiopatologia , Pós-Condicionamento Isquêmico/métodos , Aminopropionitrilo/análogos & derivados , Aminopropionitrilo/toxicidade , Aneurisma Dissecante/etiologia , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/complicações , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
12.
Transl Res ; 215: 17-30, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491372

RESUMO

The administration of geranylgeranyl pyrophosphate (GGPP) (or its precursor, geranylgeraniol [GGOH]) has been shown by several in vitro studies to be capable of abrogating statin-induced myotoxicity. Nonetheless, the potential of GGPP repletion to prevent statin-associated muscle symptoms (SAMS) in vivo is yet to be investigated. Therefore, this study aimed to evaluate the ability of GGOH to prevent SAMS in rodents. Female Wistar rats (12 weeks of age) were randomised to 1 of 4 treatment groups: control, control with GGOH, simvastatin or simvastatin with GGOH. Ex vivo assessment of force production was conducted in skeletal muscles of varying fiber composition. Ex vivo left ventricular performance and blood vessel function was also assessed to determine if the administration of GGOH caused adverse changes in these parameters. Statin administration was associated with reduced force production in fast-twitch glycolytic muscle, but coadministration with GGOH completely abrogated this effect. Additionally, GGOH improved the performance of muscles not adversely affected by simvastatin (ie, those with a greater proportion of slow-twitch oxidative fibers), and increased force production in the control animals. Neither control nor statin-treated rodents given GGOH exhibited adverse changes in cardiac function. Vascular relaxation was also maintained following treatment with GGOH. The findings of this study demonstrate that GGOH can prevent statin-induced skeletal muscle fatigue in rodents without causing adverse changes in cardiovascular function. Further studies to elucidate the exact mechanisms underlying the effects observed in this investigation are warranted.


Assuntos
Diterpenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Fadiga Muscular/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Liso Vascular/patologia , Miocárdio/patologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Fenômenos Biomecânicos/efeitos dos fármacos , Ingestão de Líquidos , Elasticidade , Comportamento Alimentar/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Nível de Saúde , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Lipídeos/sangue , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar
13.
Chin J Integr Med ; 26(3): 180-187, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883057

RESUMO

OBJECTIVE: To elevate the effects of Qingxuan Jiangya Decoction (, QXJYD) on hypertension and vascular structural remodeling (VSR) in spontaneously hypertensive rats (SHRs), and investigate the underlying mechanisms. METHODS: SHRs (n=8) were given intra-gastric administration with 60 mg/kg of QXJYD or saline, daily for 8 weeks, while rats in SHR-control (n=8) and WKY (n=8) groups were received equal volumes of saline solution. Systolic blood pressures (SBP), diastolic blood pressures (DBP) and mean blood pressures (MBP) were measured once a week. The levels of angiotensin II (Ang II), endothelin 1 (ET-1) and plasma renin activity (PRA) were tested by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. The effect of QXJYD on VSR was determined by examining the media thickness and the ex vivo contractility of thoracic aortic. The proliferation and fibrosis of vascular smooth muscle cells (VSMCs) were examined via immunohistochemical (IHC) staining for proliferating cell nuclear antigen (PCNA), collagen I and collagen III, respectively. The mRNA and protein expressions of transforming growth factor ß 1 (TGF-ß 1), Smad3 and phosphorylation of Smad3 in thoracic aorta tissues were determined by real-time polymerase chain reaction (PCR) and Western blot assay, respectively. RESULTS: QXJYD treatment led to a significant decrease of the elevation of blood pressure in SHRs and reduced the levels of Ang II, ET-1 and PRA in the serum (P<0.05). In addition, QXJYD treatment remarkably ameliorated VSR and vascular function in SHRs. Moreover, QXJYD inhibited VSMC proliferation and fibrosis by suppressing the expression of PCNA, collagen I and collagen III in thoracic aortic. Furthermore, QXJYD inhibited the expression of TGF-ß 1, Smad3 and the phosphorylation of Smad3, respectively (P<0.05). CONCLUSION: QXJYD reversed VSR by inhibiting VSMC proliferation and collagen deposition via regulation of TGF-ß 1/Smad signaling pathway, which may, in part, illuminate its anti-hypertensive activities.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hipertensão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Ratos , Ratos Endogâmicos SHR
14.
Eur J Pharmacol ; 869: 172887, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31877277

RESUMO

Pseudoprotodioscin (PPD), a phytoestrogen isolated from Dioscorea nipponica Makino, is recognized to possess anti-inflammatory and antiadipogenic capacities. However, little is known about the antiatherosclerotic effects of PPD and the underlying mechanisms. Here, the contribution of estrogen receptors (ERs) and inflammation to PPD-mediated amelioration of endothelial dysfunction has been fully assessed. PPD administration alleviated atherosclerotic lesions by lowering total cholesterol in ovariectomized apoE-/- mice fed a high-cholesterol diet. Molecular docking analysis suggested a selective interaction of PPD with ERα. Upon PPD treatment, ERα and endothelial nitric oxide synthase (eNOS) protein levels were increased, whereas cell adhesion molecule and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were suppressed in human umbilical vein endothelial cells (HUVECs) after injury caused by oxidized low-density lipoprotein (ox-LDL). These effects could be abolished by an ERα antagonist or a NOS inhibitor. Whereas, PPD can ERα-independently suppress TNFα expression in peritoneal macrophages upon LPS induction. Estrogen deficiency induced inflammatory phenotypes in perivascular adipose tissue (PAT), which could be partially attenuated by PPD. The increased release of adiponectin in PAT after PPD treatment is in accordance with previous reported data showing that adiponectin exerts anti-inflammatory effects in multiple cell types. ERα-dependent antiadipogenic effects of PPD were also detected in PAT-derived stromal cells. The present study reveals a novel mechanism through which PPD exerts estrogenic and anti-inflammatory properties in atherosclerosis-prone mice. Thus, PPD is a promising compound which has potential therapeutic effects on atherosclerotic cardiovascular diseases in postmenopausal women.


Assuntos
Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Diosgenina/análogos & derivados , Estrogênios/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Apoptose/efeitos dos fármacos , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Células Cultivadas , Quimiocina CCL2/genética , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Malondialdeído/metabolismo , Camundongos Knockout para ApoE , Simulação de Acoplamento Molecular , Óxido Nítrico Sintase Tipo III/metabolismo , Pós-Menopausa , Fator de Necrose Tumoral alfa/metabolismo
15.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1134-1135: 121854, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785534

RESUMO

Rosmarinus officinalis L., rosemary, is traditionally used to treat headache and improve cardiovascular disease partly due to its vasorelaxant activity, while the vasorelaxant ingredients remain unclear. In this study, chemical spectrum-pharmacological effect relationship (spectrum-effect relationship) was utilized for efficiently discovering the main vasorelaxant ingredients of rosemary. Ten kinds of rosemary extracts were prepared by different extracting solvents and macroporous resin purification, and their chemical components were analyzed by UPLC. At the same time, the vasorelaxant activities of the 10 kinds of rosemary extracts were estimated on isolated rat thoracic aorta, and three chemometrics named partial least squares regression (PLSR), grey correlation analysis (GRA), and the least absolute shrinkage and selection operator (LASSO) were applied to construct spectrum-effect relationship between the UPLC fingerprints and vasorelaxant activity of rosemary extracts. As a result, most rosemary extracts showed dose-dependent increase in vasorelaxant activity and five kinds of ingredients, including carnosol, carnosic acid, epirosmanol methyl ether, carnosol isomer, and augustic acid were screened as vasorelaxant ingredients. Further, the vasorelaxant activities of carnosic acid and carnosol were verified. Moreover, the increase of nitric oxide (NO) and the decrease of angiotensin-II (Ang-II) were thought to contribute to the vasorelaxant activity of rosemary.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Rosmarinus/química , Terpenos , Vasodilatadores , Animais , Aorta Torácica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Terpenos/análise , Terpenos/química , Terpenos/farmacologia , Vasodilatadores/análise , Vasodilatadores/química , Vasodilatadores/farmacologia
16.
Biol Pharm Bull ; 42(12): 2076-2082, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787722

RESUMO

The cyclitol bornesitol is the main constituent of the leaves from the antihypertensive medicinal plant Hancornia speciosa. This study aimed to investigate the ability of bornesitol to reduce blood pressure and its mechanism of action. Normotensive Wistar rats were divided into control group and bornesitol groups treated intravenously with bornesitol (0.1, 1.0 and 3.0 mg/kg). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded in non-anesthetized awake animals. Nitric oxide (NO) and angiotensin-converting enzyme (ACE) were measured in plasma by using colorimetric methods. Vascular reactivity study was performed in rat aorta rings and the involvement of nitric oxide synthase (NOS), calcium-calmodulin complex and phosphatidylinositol-3-kinase (PI3K)/Akt pathway in the vasodilator effect was investigated. Administration of bornesitol significantly reduced the SBP, increased the plasmatic level of nitrite, and decreased ACE activity in normotensive rats. In the rat aorta, bornesitol induced endothelium-dependent vasodilatation, which was abolished by NOS blockade. While calcium-calmodulin complex inhibition decreased the vasodilator effect of bornesitol, the inhibition of PI3K/Akt pathway did not alter it. Bornesitol reduced the blood pressure by a mechanism involving an increased production or bioavailability of NO, inhibition of ACE, and by an endothelium- and NO-dependent vasodilator effect. The present results support the use of bornesitol as an active marker for the cardiovascular activity of Hancornia speciosa.


Assuntos
Anti-Hipertensivos/farmacologia , Apocynaceae , Ciclitóis/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Brasil , Masculino , Óxido Nítrico/sangue , Nitritos/sangue , Peptidil Dipeptidase A/sangue , Folhas de Planta , Plantas Medicinais , Ratos Wistar
17.
PLoS One ; 14(11): e0223914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31697707

RESUMO

Much evidence indicates that metabolic syndrome is strongly correlated with a decrease in nitric oxide and an increase in oxidative stress leading to cardiovascular alterations. In recent years, gut microbiota has emerged as a new contributor to the metabolic syndrome establishment and associated cardiovascular diseases, but the underlying mechanisms remain unclear. We hypothesized that a positive modulation of cyclic guanosine monophosphate (cGMP) pathway, through phosphodiesterase type 5 (PDE5) inhibition could prevent cardiovascular alterations and gut dysbiosis that may be associated to metabolic syndrome. Spontaneously hypertensive rats (SHR) were randomly divided into 4 groups: control, cafeteria diet (CD) and sildenafil citrate treated groups (5mg/kg per os) were given either a CD or a standard chow diet for 10 weeks. Body weight, arterial blood pressure and glucose tolerance test were monitored. At the 10th week, cardiac inotropy and coronary perfusion pressure were evaluated on isolated heart according to Langendorff method. Cumulative concentration response curves to phenylephrine and acetylcholine were determined on thoracic aorta rings for vascular reactivity evaluation. Faecal samples were collected for the gut microbiota analysis. Compared to the control group, CD-fed rats showed a significant increase in body weight gain, arterial blood pressure and were glucose intolerant. This group showed also a decrease in ß-adrenoceptor-induced cardiac inotropy and coronary vasodilation. Gut microbiota analysis revealed a significant reduction in the abundance of Lactobocillus spp in cafeteria diet-fed rats when compared to the control ones. Sildenafil citrate long-term treatment decreased weight gain and arterial blood pressure, improved coronary vasodilation and reduced α1-adrenoceptor-induced vasoconstriction in CD group. However, it did not reverse gut dysbiosis induced by chronic CD feeding. These results suggest that cGMP pathway targeting may be a potential therapeutic strategy for the management of the metabolic syndrome and associated cardiovascular disorders.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Acetilcolina/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/microbiologia , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/microbiologia , GMP Cíclico/metabolismo , Dieta/métodos , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose/métodos , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/microbiologia , Fenilefrina/metabolismo , Ratos , Ratos Endogâmicos SHR , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
18.
Pharmacology ; 104(5-6): 359-367, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31484179

RESUMO

Previous studies have shown that the anti-contractile effect of the perivascular adipose tissue (PVAT) is attenuated in pregnancy. In the present investigation, we have examined the possibility that this loss of anti-contractile effect could be due to changes in calcium mobilization. PVAT exerted anti-contractile effect against 5-hydroxytryptamine (5-HT)-induced contractions of aorta segments from pregnant and non-pregnant rats and this anti-contractile effect was attenuated in segments from pregnant rats. Nifedipine (10-6 mol/L), an inhibitor of L-type dihydropyridine calcium channels, significantly reduced 5-HT-induced contraction of aorta segments from non-pregnant and pregnant rats with and without PVAT. The inhibitory effect of nifedipine against 5-HT-induced contractions was attenuated in PVAT-free aorta segments from pregnant rats. However, while PVAT reduced the effectiveness of nifedipine in aorta segments from non-pregnant rats, it partially restored the inhibitory effect of nifedipine in aorta segments from pregnant rats. Inhibitors of calcium sensitization, Y-27632 (10-6 mol/L) and GF 109203X (10-6 mol/L), significantly reduced 5-HT-induced contractions of PVAT-free aorta segments from non-pregnant and pregnant rats. Both inhibitors, however, were less effective in aorta segments from pregnant rats. The presence of PVAT reduced the effectiveness of Y-27632 and GF 109203X in aorta segments from pregnant and non-pregnant rats. Protein expression of Rho-associated protein kinase (ROCK) I and II was detected in aorta segments and PVAT from pregnant and non-pregnant rats. There was a reduction in the expression of both isoforms in aorta segments but not PVAT from pregnant rats. In addition, there was no significant difference in the expression of ROCK-I and ROCK-II in PVAT from pregnant and non-pregnant rats. We concluded that the loss of anti-contractile effect of PVAT in aorta segments from pregnant rats could be due to increased influx of extracellular calcium through nifedipine-sensitive dihydropyridine channels.


Assuntos
Tecido Adiposo/fisiologia , Aorta Torácica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/fisiologia , Nifedipino/farmacologia , Amidas/farmacologia , Animais , Aorta Torácica/fisiologia , Feminino , Indóis/farmacologia , Maleimidas/farmacologia , Gravidez , Piridinas/farmacologia , Ratos Sprague-Dawley , Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacos
20.
Toxicol Appl Pharmacol ; 381: 114710, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31415774

RESUMO

Cardiovascular diseases (CVD) are more frequent among postmenopausal women due to the decline of estrogen concentration in plasma. However, the role of the vascular modulator effect of estrogen is controversial, since it occurs both in physiological and pathological conditions, increasing or reducing vascular reactivity. As mercury is widely associated with the development of CVD, we investigated putative hazardous effects on the mechanisms that modulate vascular reactivity in aortic rings of female Wistar rats promoted by acute mercury exposure. Mercury increased vascular reactivity and oxidative stress possibly due to NADPH oxidase participation, increased production of cyclooxygenase-2 (COX-2) and thromboxane A2 (TXA2) formation. The metal also induced endothelial denudation in the aorta by reducing the bioavailability of nitric oxide (NO) and enhancing the activity of the PI3K/Akt signaling pathway. Mercury exposure also induced nuclear estrogen receptors (ERα, ERß) to act as vasoconstrictors. Our findings suggest that mercury might increase the chances of developing cardiovascular diseases in females and should be considered an important environmental risk factor.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Mercúrio/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Estrogênicos/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Núcleo Celular/fisiologia , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiologia , Feminino , Óxido Nítrico/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxidos/metabolismo
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