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1.
J Am Heart Assoc ; 9(3): e014035, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32009525

RESUMO

Background Hypothermia has been associated with therapeutic benefits including reduced mortality and better neurologic outcomes in survivors of cardiac arrest. However, undesirable side effects have been reported in patients undergoing coronary interventions. Using a large animal model of temperature management, we aimed to describe how temperature interferes with the coronary vasculature. Methods and Results Coronary hemodynamics and endothelial function were studied in 12 pigs at various core temperatures. Left circumflex coronary artery was challenged with intracoronary nitroglycerin, bradykinin, and adenosine at normothermia (38°C) and mild hypothermia (34°C), followed by either rewarming (38°C; n=6) or moderate hypothermia (MoHT; 32°C, n=6). Invasive coronary hemodynamics by Doppler wire revealed a slower coronary blood velocity at 32°C in the MoHT protocol (normothermia 20.2±11.2 cm/s versus mild hypothermia 18.7±4.3 cm/s versus MoHT 11.3±5.3 cm/s, P=0.007). MoHT time point was also associated with high values of hyperemic microvascular resistance (>3 mm Hg/cm per second) (normothermia 2.0±0.6 mm Hg/cm per second versus mild hypothermia 2.0±0.8 mm Hg/cm per second versus MoHT 3.4±1.6 mm Hg/cm per second, P=0.273). Assessment of coronary vasodilation by quantitative coronary analysis showed increased endothelium-dependent (bradykinin) vasodilation at 32°C when compared with normothermia (normothermia 6.96% change versus mild hypothermia 9.01% change versus MoHT 25.42% change, P=0.044). Results from coronary reactivity in vitro were in agreement with angiography data and established that endothelium-dependent relaxation in MoHT completely relies on NO production. Conclusions In this porcine model of temperature management, 34°C hypothermia and rewarming (38°C) did not affect coronary hemodynamics or endothelial function. However, 32°C hypothermia altered coronary vasculature physiology by slowing coronary blood flow, increasing microvascular resistance, and exacerbating endothelium-dependent vasodilatory response.

2.
Sci Rep ; 10(1): 889, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965005

RESUMO

Williams-Beuren syndrome (WBS) is a rare disorder caused by a heterozygous deletion of 26-28 contiguous genes that affects the brain and cardiovascular system. Here, we investigated whether WBS affects aortic structure and function in the complete deletion (CD) mouse model harbouring the most common deletion found in WBS patients. Thoracic aortas from 3-4 months-old male CD mice and wild-type littermates were mounted in wire myographs or were processed for histomorphometrical analysis. Nitric oxide synthase (NOS) isoforms and oxidative stress levels were assessed. Ascending aortas from young adult CD mice showed moderate (50%) luminal stenosis, whereas endothelial function and oxidative stress were comparable to wild-type. CD mice showed greater contractions to KCl. However, α1-adrenergic contractions to phenylephrine, but not with a thromboxane analogue, were compromised. Decreased phenylephrine responses were not affected by selective inducible NOS blockade with 1400 W, but were prevented by the non-selective NOS inhibitor L-NAME and the selective neuronal NOS inhibitor SMTC. Consistently, CD mice showed increased neuronal NOS expression in aortas. Overall, aortic stenosis in CD mice coexists with excessive nNOS-derived NO signaling that compromises ascending aorta α1-adrenergic contractions. We suggest that increased neuronal NOS signaling may act as a physiological 'brake' against the detrimental effects of stenosis.

3.
Cells ; 8(10)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597326

RESUMO

Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women's age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17ß-estradiol starting at the day of ovariectomy (early-onset, E2E) or 45 days after surgery (late-onset, E2L). In SAMR1, both treatments, E2E and E2L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2E: 128.1 ± 11.6; E2L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2E: 183.3 ± 11.1; E2L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA.

4.
Sci Rep ; 9(1): 11443, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391506

RESUMO

Obstructive sleep apnea syndrome (OSA) promotes aortic dilatation, increased stiffness and accelerated atherosclerosis, but the mechanisms of vascular remodelling are not known. We aimed to assess vascular remodelling, its mechanisms, and the effect of mesenchymal stem cells (MSC) infusions in a clinically relevant rat model of chronic OSA involving recurrent airway obstructions leading thoracic pressure swings and intermittent hypoxia/hypercapnia (OSA-rats). Another group of rats were placed in the same setup without air obstructions (Sham-rats) and were considered controls. Our study demonstrates that chronic, non-invasive repetitive airway obstructions mimicking OSA promote remarkable structural changes of the descending thoracic aorta such as eccentric aortic hypertrophy due to an increased wall thickness and lumen diameter, an increase in the number of elastin fibers which, in contrast, get ruptured, but no changes in tunica media fibrosis. As putative molecular mechanisms of the OSA-induced vascular changes we identified an increase in reactive oxygen species and renin-angiotensin system markers and an imbalance in oxide nitric synthesis. Our results also indicate that MSC infusion blunts the OSA-related vascular changes, most probably due to their anti-inflammatory properties.

5.
Biochem Pharmacol ; 164: 115-128, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954486

RESUMO

Uric acid (UA) is a promising protective treatment in ischaemic stroke, but the precise molecular targets underlying its in vivo beneficial actions remain unclear. High concentrations of UA inhibit angiogenesis of cultured endothelial cells via Krüppel-like factor 2 (KLF)-induced downregulation of vascular endothelial growth factor (VEGF), a pro-angiogenic mediator that is able to increase blood-brain barrier (BBB) permeability in acute stroke. Here, we investigated whether UA treatment after ischaemic stroke protects brain endothelial cell functions and modulates the KLF2-VEGF-A axis. Transient intraluminal middle cerebral artery (MCA) occlusion/reperfusion was induced in adult male spontaneously hypertensive (SHR) rats and corresponding normotensive Wistar-Kyoto (WKY) rats. Animals received UA (16 mg/kg) or vehicle (Locke's buffer) i.v. at reperfusion. BBB permeability was evaluated by Evans blue extravasation to the brain and in human cerebral endothelial hCMEC/D3 cells under oxygen-glucose deprivation/re-oxygenation. Circulating VEGF-A levels were measured in rats and acute ischaemic stroke patients from the URICO-ICTUS trial. Angiogenesis progression was assessed in Matrigel-cultured MCA. Worse post-stroke brain damage in SHR than WKY rats was associated with higher hyperaemia at reperfusion, increased Evans blue extravasation, exacerbated MCA angiogenic sprouting, and higher VEGF-A levels. UA treatment reduced infarct volume and Evans blue leakage in both rat strains, improved endothelial cell barrier integrity and KLF2 expression, and lowered VEGF-A levels in SHR rats. Hypertensive stroke patients treated with UA showed lower levels of VEGF-A than patients receiving vehicle. Consistently, UA prevented the enhanced MCA angiogenesis in SHR rats by a mechanism involving KLF2 activation. We conclude that UA treatment after ischaemic stroke upregulates KLF2, reduces VEGF-A signalling, and attenuates brain endothelial cell dysfunctions leading to neuroprotection.

6.
Rev. esp. cardiol. (Ed. impr.) ; 72(4): 317-323, abr. 2019. tab, graf
Artigo em Espanhol | IBECS-Express | ID: ibc-ET1-4282

RESUMO

Introducción y objetivos: En el infarto agudo de miocardio con elevación del segmento ST, el ADN libre circulante podría originarse de los leucocitos activados en la lesión coronaria. El objetivo fue investigar la relación entre el ADN libre y la reperfusión coronaria. Métodos: Se incluyó a 116 pacientes, tratados con angioplastia primaria y tromboaspiración. Se cuantificó el ADN libre coronario (durante la aspiración) y periférico (al final del procedimiento), así como la troponina T ultrasensible y la mieloperoxidasa. El objetivo primario fue la no resolución del segmento ST (RST) (≥ 70%) y el secundario la ausencia de flujo Thrombolysis In Myocardial Infarction 3 (TIMI 3) final. Resultados: Se obtuvo RST en 51 (44%) pacientes y flujo TIMI 3 en 97 (84%). Los pacientes sin RST y flujo TIMI 3 tuvieron un menor gradiente ADN libre periférico-coronario (p = 0,02 y p = 0,04, respectivamente). Un gradiente pequeño de ADN libre (< 1,82 ng/ml) se asoció a una mayor frecuencia de no RST (65 frente al 30%; p = 0,001) y de falta de flujo TIMI 3 (21 frente al 3%; p = 0,05. Tras el ajuste multivariable, un gradiente de ADN libre pequeño fue predictivo de no RST (OR = 4,50; IC95%, 1,60-12,62; p = 0,004), en tanto que hubo una tendencia no significativa para el flujo TIMI 3 (p = 0,14). El ADN libre no se correlacionó con la troponina o la mieloperoxidasa. Conclusiones: Un gradiente pequeño de ADN libre periférico-coronario, como expresión de una alta carga de ADN libre coronario, se asocia con no RST en el infarto agudo de miocardio. El ADN libre coronario podría reflejar la activación de los neutrófilos. La potencial contribución de este fenómeno al fracaso de la tromboaspiración requiere nuevos estudios


Introduction and objectives: Cell-free DNA (cfDNA) in ST-segment elevation myocardial infarction might originate from hyperactivated leukocytes at the coronary lesion. Our aim was to investigate the relationship between cfDNA and coronary reperfusion. Methods: We studied 116 patients treated with primary angioplasty using thrombus aspiration. Coronary (during aspiration) and peripheral (at the end of the procedure) blood samples were drawn for cfDNA, as well as high-sensitivity troponin T and myeloperoxidase quantification. The primary endpoint was no ST-segment resolution (STR) (≥ 70%) and the secondary endpoint was lack of final Thrombolysis In Myocardial Infarction flow 3 (TIMI 3). Results: ST-segment resolution was achieved in 51 (44%) patients and TIMI 3 flow in 97 (84%). Patients without STR and TIMI 3 flow had a smaller peripheral-coronary cfDNA gradient (P = .02 and P = .04 respectively). A small cfDNA gradient (< 1.82 ng/mL) was associated with a higher rate of no STR (65% vs 30%; P = .001) and lack of TIMI 3 flow (21% vs 3%; P = .05). After multivariable adjustment, the small cfDNA gradient was predictive of no STR (OR, 4.50; 95%CI, 1.60-12.62; P = .004), while there was a nonsignificant trend for final TIMI 3 flow (P = .14). Cell-free DNA levels did not correlate with troponin T or myeloperoxidase. Conclusions: A small peripheral-coronary cfDNA gradient, as an expression of high coronary cfDNA burden, is associated with no STR in acute myocardial infarction. Intracoronary cfDNA might reflect neutrophil activation. Whether this phenomenon contributes to thrombus aspiration failure requires further study

7.
Basic Res Cardiol ; 114(2): 5, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635778

RESUMO

There is scarce evidence for pulmonary artery denervation (PADN) as a potential treatment for chronic postcapillary pulmonary hypertension (PH). We aimed to perform a proof-of-concept of PADN in a translational model of chronic PH. Nineteen pigs with chronic postcapillary PH (secondary to pulmonary vein banding) were randomized to surgical-PADN (using bipolar radiofrequency clamps) or sham procedure. Additionally, 6 healthy animals underwent percutaneous-PADN to compare the pulmonary artery (PA) lesion generated with both approaches. In the surgical-PADN arm, hemodynamic evaluation and cardiac magnetic resonance (CMR) were performed at baseline and at 2 and 3-month follow-up. Histological assessment was carried out at the completion of the protocol. Eighteen pigs (6 following surgical-PADN, 6 sham and 6 percutaneous-PADN) completed the protocol. A complete transmural PA lesion was demonstrated using surgical clamps, whereas only focal damage to adventitial fibers was observed after percutaneous-PADN. In the surgical-PADN arm, the hemodynamic profile did not significantly differ between groups neither at baseline [mean pulmonary artery pressure (mPAP) median values of 32.0 vs. 27.5 mmHg, P = 0.394 and indexed pulmonary vascular resistance (iPVR) 5.9 vs. 4.7 WU m2, P = 0.394 for PADN/sham groups, respectively] nor at any follow-up (mPAP of 35.0 vs. 35.0 mmHg, P = 0.236 and iPVR of 8.3 vs. 6.7 WU m2, P = 0.477 at third month in PADN/sham groups, respectively). Surgical-PADN was not associated with any benefit in RV anatomy or function on CMR/histology. In a large-animal model of chronic postcapillary PH, transmural PADN with surgical clamps was associated with a neutral pulmonary hemodynamic effect.


Assuntos
Denervação/métodos , Hipertensão Pulmonar , Artéria Pulmonar/inervação , Artéria Pulmonar/cirurgia , Animais , Modelos Animais de Doenças , Distribuição Aleatória , Suínos , Pesquisa Médica Translacional
8.
Rev Esp Cardiol (Engl Ed) ; 72(4): 317-323, 2019 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29655768

RESUMO

INTRODUCTION AND OBJECTIVES: Cell-free DNA (cfDNA) in ST-segment elevation myocardial infarction might originate from hyperactivated leukocytes at the coronary lesion. Our aim was to investigate the relationship between cfDNA and coronary reperfusion. METHODS: We studied 116 patients treated with primary angioplasty using thrombus aspiration. Coronary (during aspiration) and peripheral (at the end of the procedure) blood samples were drawn for cfDNA, as well as high-sensitivity troponin T and myeloperoxidase quantification. The primary endpoint was no ST-segment resolution (STR) (≥ 70%) and the secondary endpoint was lack of final Thrombolysis In Myocardial Infarction flow 3 (TIMI 3). RESULTS: ST-segment resolution was achieved in 51 (44%) patients and TIMI 3 flow in 97 (84%). Patients without STR and TIMI 3 flow had a smaller peripheral-coronary cfDNA gradient (P = .02 and P = .04 respectively). A small cfDNA gradient (< 1.82 ng/mL) was associated with a higher rate of no STR (65% vs 30%; P = .001) and lack of TIMI 3 flow (21% vs 3%; P = .05). After multivariable adjustment, the small cfDNA gradient was predictive of no STR (OR, 4.50; 95%CI, 1.60-12.62; P = .004), while there was a nonsignificant trend for final TIMI 3 flow (P = .14). Cell-free DNA levels did not correlate with troponin T or myeloperoxidase. CONCLUSIONS: A small peripheral-coronary cfDNA gradient, as an expression of high coronary cfDNA burden, is associated with no STR in acute myocardial infarction. Intracoronary cfDNA might reflect neutrophil activation. Whether this phenomenon contributes to thrombus aspiration failure requires further study.


Assuntos
Ácidos Nucleicos Livres/metabolismo , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Feminino , Humanos , Leucócitos/fisiologia , Ativação Linfocitária/fisiologia , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Reperfusão Miocárdica/efeitos adversos , Traumatismo por Reperfusão Miocárdica/patologia , Peroxidase/metabolismo , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Resultado do Tratamento , Troponina T/metabolismo
9.
Steroids ; 141: 46-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30458188

RESUMO

Conjugated equine estrogens (CEE) have been widely used by women who seek to relieve symptoms of menopause. Despite evidence describing protective effects against risk factors for cardiovascular diseases by naturally occurring estrogens, little is known about the vascular effects of equilin, one of the main components of CEE and not physiologically present in women. In this regard, the present study aims to compare the vascular effects of equilin in an experimental model of hypertension with those induced by 17ß-estradiol. Resistance mesenteric arteries from female spontaneously hypertensive rats (SHR) were used for recording isometric tension in a small vessel myograph. As effectively as 17ß-estradiol, equilin evoked a concentration-dependent relaxation in mesenteric arteries from female SHRs contracted with KCl, U46619, PDBu or ET-1. Equilin-induced vasodilation does not involve classical estrogen receptor activation, since the estrogen receptor antagonist (ICI 182,780) failed to inhibit relaxation in U46619-precontracted mesenteric arteries. Vasorelaxation was not affected by either endothelium removal or by inhibiting the release or action of endothelium-derived factors. Incubation with L-NAME (NOS inhibitor), ODQ (guanylyl cyclase inhibitor) or KT5823 (inhibitor of protein kinase G) did not affect equilin-induced relaxation. Similarly, indomethacin (COX inhibitor) or blockage of potassium channels with tetraethylammonium, glibenclamide, 4-aminopyridine, or ouabain did not affect equilin-induced relaxation. Inhibitors of adenylyl cyclase SQ22536 or protein kinase A (KT5720) also had no effects on equilin-induced relaxation. While 17ß-estradiol inhibited calcium (Ca2+) -induced contractions in high-K+ depolarization medium in a concentration-dependent manner, equilin induced a slight rightward-shift in the contractile responses to Ca2+. Comparable pattern of responses were observed in the concentration-response curves to (S)-(-)-Bay K 8644, a L-type Ca2+ channel activator. Equilin was unable to block the transitory contraction produced by caffeine-induced Ca2+ release from intracellular stores. In conclusion, equilin blocks L-type Ca2+ channels less effectively than 17ß-estradiol. Despite its lower effectiveness, equilin equally relaxes resistance mesenteric arteries by blocking Ca2+ entry on smooth muscle.


Assuntos
Cálcio/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Equilina/farmacologia , Estradiol/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Retículo Endoplasmático/metabolismo , Feminino , Ratos , Ratos Endogâmicos SHR
10.
Transl Stroke Res ; 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30219993

RESUMO

Hypertension is the most important modifiable risk factor for stroke and is associated with poorer post-stroke outcomes. The antioxidant uric acid is protective in experimental normotensive ischaemic stroke. However, it is unknown whether this treatment exerts long-term protection in hypertension. We aimed to evaluate the impact of transient intraluminal middle cerebral artery (MCA) occlusion (90 min)/reperfusion (1-15 days) on brain and vascular damage progression in adult male Wistar-Kyoto (WKY; n = 36) and spontaneously hypertensive (SHR; n = 37) rats treated (i.v./120 min post-occlusion) with uric acid (16 mg kg-1) or vehicle (Locke's buffer). Ischaemic brain damage was assessed longitudinally with magnetic resonance imaging and properties of MCA from both hemispheres were studied 15 days after stroke. Brain lesions in WKY rats were associated with a transitory increase in circulating IL-18 and cerebrovascular oxidative stress that did not culminate in long-term MCA alterations. In SHR rats, more severe brain damage and poorer neurofunctional outcomes were coupled to higher cortical cerebral blood flow at the onset of reperfusion, a transient increase in oxidative stress and long-lasting stroke-induced MCA hypertrophic remodelling. Thus, stroke promotes larger brain and vascular damage in hypertensive rats that persists for long-time. Uric acid administered during early reperfusion attenuated short- and long-term brain injuries in both normotensive and hypertensive rats, an effect that was associated with abolishment of the acute oxidative stress response and prevention of stroke-induced long-lasting MCA remodelling in hypertension. These results suggest that uric acid might be an effective strategy to improve stroke outcomes in hypertensive subjects.

11.
Front Physiol ; 9: 490, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867542

RESUMO

Postmenopausal period has been associated to different symptoms such as hot flashes, vulvovaginal atrophy, hypoactive sexual desire disorder (HSDD) and others. Clinical studies have described postmenopausal women presenting HSDD can benefit from the association of testosterone to conventional hormonal therapy. Testosterone has been linked to development of cardiovascular diseases including hypertension and it also increases cytochrome P-450-induced 20-HETE synthesis which in turn results in vascular dysfunction. However, the effect of testosterone plus estrogen in the cardiovascular system is still very poorly studied. The aim of the present study is to evaluate the role of cytochrome P-450 pathway in a postmenopausal hypertensive female treated with testosterone plus estrogen. For that, hypertensive ovariectomized rats (OVX-SHR) were used as a model of postmenopausal hypertension and four groups were created: SHAM-operated (SHAM), ovariectomized SHR (OVX), OVX treated for 15 days with conjugated equine estrogens [(CEE) 9.6 µg/Kg/day/po] or CEE associated to testosterone [(CEE+T) 2.85 mg/kg/weekly/im]. Phenylephrine-induced contraction and generation of reactive oxygen species (ROS) were markedly increased in aortic rings from OVX-SHR compared to SHAM rats which were restored by CEE treatment. On the other hand, CEE+T abolished vascular effects by CEE and augmented both systolic and diastolic blood pressure of SHR. Treatment of aortic rings with the CYP/20-HETE synthesis inhibitor HET0016 (1 µM) reduced phenylephrine hyperreactivity and the augmented ROS generation in the CEE+T group. These results are paralleled by the increased CYP4F3 protein expression and activity in aortas of CEE+T. In conclusion, we showed that association of testosterone to estrogen therapy produces detrimental effects in cardiovascular system of ovariectomized hypertensive females via CYP4F3/20-HETE pathway. Therefore, our findings support the standpoint that the CYP/20-HETE pathway is an important therapeutic target for the prevention of cardiovascular disease in menopausal women in the presence of high levels of testosterone.

12.
Cell Physiol Biochem ; 45(5): 1878-1892, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29510375

RESUMO

BACKGROUND/AIMS: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERα, ERß and GPER) in the regulation of miRNA expression by estrogen. METHODS: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cells (HUVEC) exposed to a physiological concentration of estradiol (E2; 1 nmol/L) for 24 hours. miRNA-gene interactions were computationally predicted using Ingenuity Pathway Analysis and changes in miRNA levels were validated by qRT-PCR. Role of ER in the E2-induced miRNA was additionally confirmed by using specific ER agonists and antagonists. RESULTS: miRNA array revealed that expression of 114 miRNA were significantly modified after E2 exposition. Further biological pathway analysis revealed cell death and survival, lipid metabolism, reproductive system function, as the top functions regulated by E2. We validated changes in the most significantly increased (miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p) and decreased (miR-378h and miR-1244) miRNA and the role of ER in these E2-induced miRNA was determined. Results showed that both classical, ERα and ERß, and membrane-bound ER, GPER, differentially regulated specific miRNA. In silico analysis of validated miRNA promoters identified specific ER binding sites. CONCLUSION: Our findings identify differentially expressed miRNA pathways linked to E2 in human endothelial cells through ER, and provide new insights by which estrogen can modulate endothelial function.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Estradiol/farmacologia , MicroRNAs/metabolismo , Regulação para Cima/efeitos dos fármacos , Células Cultivadas , Análise por Conglomerados , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/química , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo
13.
Rev. Enferm. Atual In Derme ; 86(Edição Especial)2018.
Artigo em Português | BDENF - Enfermagem | ID: biblio-1025183

RESUMO

O objetivo é descrever e analisar as evidências cientificas acerca de lesões de pele em recém-nascido. Buscouse produções científicas tendo como critérios de inclusão publicações período de 2012 a 2017, que correlacionassem os descritores "pele", "ferimentos e lesões" e "recém-nascido". As bases de dados pesquisadas foram PUBMED, WEB OF SCIENCE, LILACS, CINAHL e SCIELO. Ao analisarem-se os 10 estudos selecionados, foi consenso entre os autores que a produção de conhecimento científico referente à temática de lesões de pele em RN representa um eixo norteador para a assistência. A integridade da pele é de grande importância para a sobrevida do RN. Em virtude da sua atuação entre os órgãos internos e o meio externo, a pele atua como barreira contra infecção. Os fatores de risco para lesões de pele em RN estão associados aos procedimentos realizados no atendimento hospitalar. Conclui se que na literatura pesquisada, estudos que abordem os cuidados com a pele do RN diante de lesões ainda são escassos, portanto, faz-se necessário desenvolver novos estudos nesse sentido


The objective is to describe and analyze the scientific evidence about skin lesions in newborns. It was searched for scientific productions having as criteria of inclusion publications period from 2012 to 2017, that correlated the descriptors "skin", "injuries and lesions" and "newborn". The searched databases were PUBMED, WEB OF SCIENCE, LILACS, CINAHL and SCIELO. When analyzing the 10 selected studies, it was agreed among the authors that the production of scientific knowledge regarding the theme of skin lesions in NB represents a guiding axis for the care. The integrity of the skin is of great importance for the survival of the newborn. Due to its action between the internal organs and the external environment, the skin acts as a barrier against infection. Risk factors for skin lesions in newborns are associated with procedures performed in hospital care. It is concluded that in the researched literature, studies that address the skin care of the newborn with lesions are still scarce, therefore, it is necessary to develop new studies in this sense


Assuntos
Humanos , Pele , Ferimentos e Lesões , Recém-Nascido , Enfermagem
14.
J Am Heart Assoc ; 6(5)2017 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-28468789

RESUMO

BACKGROUND: Autologous adipose tissue-derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post-myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long-term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance. METHODS AND RESULTS: Thirty-eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow-ups were performed at short (2 days after acute myocardial infarction vehicle-treated, n=10; ATMSCs-treated, n=9) or long term (60 days after acute myocardial infarction vehicle-treated, n=7; ATMSCs-treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs-treated animals (48.6±6% versus 55.9±5.7% in vehicle; P=0.017); enhancement of the reparative process with up-regulated vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and stromal-derived factor-1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle; P=0.016). In long-term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day-7 and day-60 cardiac magnetic resonance studies in ATMSCs-treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days; P=0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days; P=0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs-treated animals (118±18 versus 92.4±24.3 vessels/mm2 in vehicle; P=0.045). Cardiac magnetic resonance-measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point. CONCLUSIONS: In this porcine acute myocardial infarction model, allogeneic ATMSCs-based therapy was associated with increased cardioprotective and reparative mechanisms and with better cardiac magnetic resonance-measured perfusion. No effect on left ventricular volumes or ejection fraction was observed.


Assuntos
Tecido Adiposo/citologia , Circulação Coronária , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais , Infarto do Miocárdio/cirurgia , Disfunção Ventricular Esquerda/cirurgia , Função Ventricular Esquerda , Proteínas Angiogênicas/metabolismo , Animais , Células Cultivadas , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imagem por Ressonância Magnética , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/metabolismo , Tomografia Computadorizada Multidetectores , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Neovascularização Fisiológica , Imagem de Perfusão/métodos , Recuperação de Função Fisiológica , Regeneração , Sus scrofa , Fatores de Tempo , Transfecção , Transplante Homólogo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
15.
J Pharmacol Exp Ther ; 362(1): 98-107, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28533289

RESUMO

Standard hormone therapy for menopausal women [conjugated equine estrogen (CEE) 0.625 mg] has been associated with increased risk of venous thrombosis. Regimens containing a lower CEE dose (0.30 mg) have been used clinically to decrease side effects of supraphysiologic doses of estrogen. In this study, we determined the effects of standard (SD) and low dose (LD) of CEE on venular function in ovariectomized (OVX) spontaneously hypertensive rats (SHR). Contractions by angiotensin-II (Ang-II 10 µM) in perfused mesenteric venular bed were markedly increased in OVX (21.5 ± 1.3 mmHg) compared with Sham (14.7 ± 1.1 mm Hg, P < 0.05). CEE-SD did not modify Ang-II responses in OVX, whereas CEE-LD restored Ang-II contraction to Sham levels. Endothelial nitric oxide synthase (eNOS) inhibition by L-NAME increased Ang-II contractions in Sham and CEE-LD and was without effect in venules of OVX SHR and CEE-SD. In OVX there was decreased NO generation in association with diminished eNOS phosphorylation and increased O2- generation in the venular wall. CEE-LD reverted the deleterious effects of ovariectomy. Although CEE-SD augmented eNOS phosphorylation in OVX, it was unable to increase NO levels, probably owing to its inability to reduce O2- Distinct effects by CEE-SD and CEE-LD parallel the differential modulation of Ang-II and estrogen receptors. Compared with Sham, CEE-LD increases Ang II receptor type 2, whereas CEE-SD modified ERß expression in the venous bed. Interestingly, both CEE doses increased G protein-coupled estrogen receptor in OVX. Our data suggest that estrogen dose is an important factor for venous function. Although CEE-LD reversed deleterious effects of OVX, CEE-SD showed null effects despite its ability to increase eNOS activity.


Assuntos
Angiotensina II/farmacologia , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios Conjugados (USP)/farmacologia , Pós-Menopausa/metabolismo , Receptores Estrogênicos/biossíntese , Circulação Esplâncnica/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Cavalos , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Ovariectomia , Ratos Endogâmicos SHR , Receptor Tipo 2 de Angiotensina/efeitos dos fármacos
16.
Int J Cardiol ; 232: 70-75, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28087172

RESUMO

BACKGROUND: Therapeutic hypothermia (HT) in out-of-hospital cardiac arrest STEMI patients aims to improve their neurological prognosis, but it has been associated with slow coronary flow and cardiac thrombotic events. We sought to serially assess endothelial function during the first 48h after admission in out-of-hospital cardiac arrest STEMI patients, under therapeutic hypothermia (HT). METHODS: From January 2015 to August 2015, eighteen consecutive out-of-hospital cardiac arrest STEMI patients eligible for primary PCI received HT at admission and were included in the study (HT group). During the same time period, eight consecutive patients with large anterior STEMI who received primary PCI but not HT were included as control group. Serial endothelial function by measuring flow-mediated dilatation (FMD) in the brachial artery, biomarkers of endothelial function and oxidative stress were assessed during the first 48h after admission in both groups. RESULTS: HT group showed worse FMD as compared to the control group (p<0.001). Glutathione peroxidase-3 (GPx-3) values were higher in control as compared to HT group (p=0.019), without any interaction between time of observation and HT (p=0.864). A significant interaction between time and HT was found in the levels of sVCAM-1, which reached an earlier peak in control than in HT group (p=0.019). ET-1 values generally increase overtime (p=0.005), but without any main effect of HT (p=0.175). CONCLUSIONS: HT is associated with endothelial dysfunction in out-of-hospital cardiac arrest STEMI patients during the first 48h after admission. This vascular dysfunction may be related to increased oxidative stress due to deficiency of GPx-3 in HT patients.


Assuntos
Endotélio Vascular/fisiopatologia , Hipotermia Induzida/métodos , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Vasodilatação/fisiologia , Angiografia Coronária , Eletrocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/etiologia , Parada Cardíaca Extra-Hospitalar/terapia , Prognóstico , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia
18.
Exp Gerontol ; 85: 71-80, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27713002

RESUMO

Aging is a cardiovascular risk factor partially related to activation of the Renin-Angiotensin System (RAS). RAS activation is also influenced by sex. In this regard, our study aims to determine whether sex-associated differences in RAS contribute to a differential regulation of vascular aging and associated dysfunction. Male and female outbreed CD-1 mice were studied at 3 and 12months of age (M). Contribution of RAS was determined by treating mice from 3M to 12M with the AngII type 1 receptor blocker losartan (0.6g/L in the drinking water). At 12M, contractions to AngII were higher in males compared to females (P<0.05). This effect was paralleled by a decrease in AngII type 2 receptors in 12M males. Aging also diminished ACh relaxation in males, but did not modify female responses. Treatment of aortas with indomethacin (10µM) restored the impaired endothelium-dependent relaxation in 12M males, suggesting an increase of cyclooxygenase (COX)-derived vasoconstrictors in aged males. Chronic treatment of mice with losartan also improved endothelium-dependent relaxation. Besides, losartan significantly decreased COX-2 expression and activity in 12M male, with a minor effect in aged females. Aging increases AngII contraction and induces endothelial dysfunction differently in males and females. In aged males, RAS contributed to increased COX-2 expression and activity, which in turn may lead to vascular dysfunction.


Assuntos
Envelhecimento/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina II/metabolismo , Prostaglandinas/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Fatores Sexuais , Animais , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Feminino , Indometacina/farmacologia , Losartan/farmacologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
19.
Exp Gerontol ; 76: 1-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26774228

RESUMO

This study investigates the effects of aging and/or ovariectomy on vascular reactivity to thromboxane A2 (TXA2) receptor stimulation with U46619, and the modulation by nitric oxide (NO) and cyclooxygenase (COX) in aorta from female senescence-accelerated mice (SAMP8) and from senescence resistant mice (SAMR1). Five-month-old female SAMR1 and SAMP8 were divided into three groups: sham-operated, ovariectomized and ovariectomized plus estradiol. Twenty-eight days after surgery, thoracic aortic rings were mounted for isometric recording of tension and concentration-response curves for U46619 (10(-10)-3 × 10(-7) M) were performed in the absence and in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) and/or COX inhibitor indomethacin (10(-5)M). Vascular superoxide production was detected by dihydroethidium staining on sections of thoracic aorta. NO bioavailability in response to U46619 was suppressed by estrogen withdrawn in young and senescent mice and was restored by the administration of estradiol. In the presence of indomethacin, contractions to U46619 decreased in all groups indicating an aging- and estrogen-dependent modulation of contractile prostanoids. The simultaneous incubation of L-NAME and indomethacin did not change the maximal responses and sensitivities to TXA2 in any group in comparison with untreated aortic segments. The superoxide generation induced by TXA2 was greater in aorta from SAMP8 than in SAMR1. Moreover, in ovariectomized groups superoxide production was further increased and treatment with 17ß-estradiol reverted the effects of the ovariectomy. Inhibition of COX with indomethacin prevented the U46619-induced increase in superoxide formation. Our results indicate that NO bioavailability in response to TP receptor activation is both estrogen- and aging-dependent. TXA2 induced contractions are partially mediated by COX activation. Both aging and ovariectomy enhanced COX-dependent component of the TXA2-induced contraction. It is noteworthy that in the absence of estrogen, COX inhibition induces an increase of NO bioavailability. Therefore, in senescent female mice with an experimental menopause, TP-receptor stimulation is responsible for COX activation and enhanced superoxide generation, which may result in reduced NO bioavailability. These effects were reversed by estrogen administration.


Assuntos
Envelhecimento/metabolismo , Aorta Torácica/enzimologia , Menopausa/metabolismo , Óxido Nítrico/metabolismo , Ovariectomia , Prostaglandina-Endoperóxido Sintases/metabolismo , Vasoconstrição , Fatores Etários , Animais , Aorta Torácica/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Ativação Enzimática , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Camundongos , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo , Receptores de Tromboxanos/agonistas , Receptores de Tromboxanos/metabolismo , Transdução de Sinais , Superóxidos/metabolismo , Tromboxano A2/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
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