53,458 research outputs found
Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy
No full textMaternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system
Diferentes espécies reativas e neurotransmissores modulam os efeitos hipotensores da Ang II e Ang-(1-7) na CVLM em ratos com hipertensão renovascular 2R1C.
No full textPrograma de Pós-Graduação em Ciências Biológicas. Núcleo de Pesquisas em Ciências Biológicas, Pró-Reitoria de Pesquisa de Pós Graduação, Universidade Federal de Ouro Preto.A hipertensão está associada com uma disfunção do sistema renina-angiotensina
(SRA) e aumento do estresse oxidativo no bulbo ventrolateral caudal (CVLM). Estudos
mostraram que a microinjeção de angiotensina (Ang) Ang II e Ang-(1-7) na CVLM
induzem efeitos hipotensores similares em ratos normotensos SHAM e com hipertensão
renovascular 2R1C. Em adição, tem sido descrito que o ânion superóxido (O2•-) participa
dos efeitos da Ang II, enquanto que o óxido nítrico (NO) modula as ações da Ang-(1-7) em
regiões periféricas e centrais e que os neurotransmissores aminoácidos participam dos
efeitos das angiotensinas em áreas centrais. Assim, o objetivo do presente estudo foi avaliar
se diferentes espécies reativas (ER) como O2•- e NO e neurotransmissores como glutamato e
GABA estariam envolvidos nos efeitos hipotensores induzidos pelas microinjeções de Ang
II e Ang-(1-7) na CVLM em ratos 2R1C. Após 28 dias da cirurgia SHAM e 2R1C, ratos
Fischer foram anestesiados (uretana, 1,2 g/kg, ip), posicionados em um aparelho
estereotáxico para procedimento de microinjeção de drogas na CVLM e instrumentados
para registro da pressão arterial média (PAM) e frequência cardíaca (FC). Ang II (40 pmol)
ou Ang-(1-7) (40 pmol) foram microinjetadas na CVLM antes e 5, 15 e 30 minutos (min)
após a microinjeção de L-NAME (inibidor não específico da óxido nítrico síntase, NOS, 10
nmol) ou vitamina C (VIT C, antioxidante ácido ascórbico, 10 nmol) ou bicuculina (BIC, antagonista do receptor GABAA, 10 pmol) ou ácido quinurênico (KYN, antagonista dos
receptores ionotrópicos do glutamato, 5 nmol) em ratos SHAM e 2R1C. A microinjeção de
Ang II e Ang-(1-7) na CVLM induziu efeito hipotensor similar em ratos SHAM e 2R1C. A
microinjeção de L-NAME na CVLM produziu queda similar na PAM e FC em ratos
SHAM e 2R1C. Enquanto, a microinjeção de VIT C na CVLM produziu queda na PAM e
FC somente em ratos 2R1C. A microinjeção de BIC na CVLM produziu queda na PAM e
FC em ratos SHAM e 2R1C. No entanto, o efeito hipotensor induzido pela microinjeção de
BIC na CVLM foi maior nos animais 2R1C comparado aos animais SHAM. Já, a
microinjeção de KYN na CVLM produziu aumento na PAM e FC em ratos SHAM e 2R1C.
Em adição, a microinjeção de L-NAME na CVLM aumentou o efeito hipotensor da Ang-(1-7) por até 45 min em ratos SHAM e por apenas 5 min em ratos 2R1C e não alterou o
efeito hipotensor da Ang II na CVLM em ratos SHAM e 2R1C. Ao contrário, a VIT C aboliu por até 15 min o efeito hipotensor da Ang II na CVLM em ratos SHAM e 2R1C e
não alterou o efeito hipotensor da Ang-(1-7) na CVLM em ambos os grupos. Além disso, a
BIC diminui o efeito hipotensor da Ang-(1-7) por até 30 min em ratos SHAM e por apenas
5 min em ratos 2R1C e não alterou o efeito hipotensor da Ang II na CVLM em ratos
SHAM e 2R1C. Já, o KYN aumentou o efeito hipotensor da Ang II por até 15 min em ratos
SHAM e 2R1C e não alterou o efeito hipotensor da Ang-(1-7) na CVLM em ambos os
grupos. Nossos dados em conjunto mostram a participação do O2
•- e do GABA na CVLM
na hipertensão renovascular 2R1C. Além disso, os efeitos hipotensores similares induzidos
pela Ang II e Ang-(1-7) na CVLM ocorrem através de mecanismos distintos, sendo que, o
NO e o GABA participam predominantemente do efeito hipotensor da Ang-(1-7), enquanto
o O2•- e o glutamato participam predominantemente do efeito hipotensor da Ang II na
CVLM em ratos normotensos e hipertensos 2R1C. Esses dados mostram que diferentes vias
e/ou mediadores intracelulares estão envolvidos nos efeitos induzidos pela Ang II e Ang-(1-7) na CVLM.Hypertension is associated with a dysfunction of the renin-angiotensin system (RAS) and
increased oxidative stress in the caudal ventrolateral medulla (CVLM). Studies showed that
microinjection of angiotensin (Ang) Ang II and Ang-(1-7) in the CVLM induce
hypotensive effects similar in SHAM normotensive and with 2K1C renovascular
hypertension rats. In addition, it has been reported that superoxide anion (O2
•-) participates
in the effects of Ang II, whereas nitric oxide (NO) modulates the actions of Ang-(1-7) in
peripheral and central regions and that the amino acid neurotransmitters participate in the
effects of angiotensins in the central areas. Thereby, the objective of the present study was
to evaluate whether different reactive species (RS) as O2•- and NO and neurotransmitters as
glutamate and GABA were involved in the hypotensives effects induced by microinjections
of Ang II and Ang-(1-7) in the CVLM in 2K1C rats. 28 days after surgery 2K1C and
SHAM, Fischer rats were anesthetized (urethane, 1.2 g/kg, ip), positioned in a stereotaxic
apparatus for procedure of drugs microinjection in CVLM and instrumented to record mean
arterial pressure (MAP) and heart rate (HR). Ang II (40 pmol) or Ang-(1-7) (40 pmol) were
microinjected in the CVLM before and 5, 15 and 30 minutes (min) after microinjection of
L-NAME (non-specific inhibitor of nitric oxide synthase, NOS, 10 nmol) or vitamin C
(VIT C, ascorbic acid antioxidant, 10 nmol) or bicuculline (BIC, GABAA receptor
antagonist, 10 pmol) or kynurenic acid (KYN, ionotropic glutamatergic receptor antagonist,
5 nmol) in SHAM and 2K1C rats. CVLM microinjection of Ang II and Ang-(1-7) induced
similar hypotensive effect in SHAM and 2K1C rats. CVLM microinjection of L-NAME
produced similar fall in MAP and HR in SHAM and 2K1C rats, while CVLM
microinjection of VIT C produced fall in MAP and HR only in 2K1C rats. CVLM
microinjection of BIC produced fall in MAP and HR in SHAM and 2K1C rats. However,
the hypotensive effect induced by microinjection of BIC in the CVLM was higher in 2K1C
animals compared to SHAM animals. Already, the CVLM microinjection of KYN
produced an increase in MAP and HR in SHAM and 2K1C rats. In addition, CVLM
microinjection of L-NAME increased the hypotensive effect of Ang-(1-7) up to 45 min in
SHAM rats and up to 5 min in 2K1C rats and did not alter the hypotensive effect induced
by CVLM microinjection of Ang II in SHAM and 2K1C rats. In contrast, VIT C abolished
up to 15 minutes the hypotensive effect of Ang II in the CVLM in 2K1C and SHAM rats
and did not change the hypotensive effect of Ang-(1-7) in the CVLM in both groups.
Furthermore, the BIC decreases the hypotensive effect of Ang-(1-7) up to 30 min in SHAM
rats and up to 5 min in 2K1C rats and did not alter the hypotensive effect of Ang II in the
CVLM in SHAM and 2K1C rats. Already, KYN increased hypotensive effect of Ang II up
to 15 min in SHAM and 2K1C rats and did not change the hypotensive effect of Ang-(1-7)
in the CVLM in both groups. Our data show the participation of the O2•- and GABA in the
CVLM in 2K1C renovascular hypertension. Moreover, similar hypotensives effects
induced by Ang II and Ang-(1-7) in the CVLM occur through distinct mechanisms, being
that, NO and GABA predominantly participate hypotensive effect of Ang-(1 -7), while the
O2•- and glutamate predominantly participate in the hypotensive effect of Ang II in the
CVLM in normotensive and 2K1C hypertensive rats. These data show that different
pathways and/or intracellular mediators are involved in the effects induced by Ang II and
Ang-(1-7) in the CVLM
Empagliflozin treatment does not affect the hypertensive response to Ang II administration to rats but decreases oxidative stress in the arterial wall, and endothelial and cardiac dysfunction
No full textBackground Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular disease independently of glycemic control. Angiotensin II (Ang II) and H2O2 have been shown to be strong inducers of the expression of SGLT2 and 1 in endothelial cells promoting oxidative stress and endothelial dysfunction. Purpose This study examined the cardiovascular protective effect of empagliflozin (empa) in a normoglycemic experimental model of hypertension in the rat. Methods Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by sphygmomanometry, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, and the level of oxidative stress using dihydroethidium staining. Results Angiotensin II administration increased systolic blood pressure from about 130 to 180 mmHg, which was not affected by the empa treatment. The 4-week Ang II treatment did not significantly affect the systolic cardiac function (cardiac output, left ventricle ejection fraction) but impaired the diastolic function as indicated by a reduced E' and IVRT values, and an increased E/E' value. The Ang II treatment increased significantly the heart and right ventricle weight whereas the left ventricle + septum weight was slightly but not significantly increased. No such functional and structural changes were observed in the Ang II + empa treatment group. An increased immunofluorescence eNOS signal in the endothelium, and a higher level of ROS throughout the aorta wall were observed in the Ang II-treated group, both of which were significantly reduced in the empa + Ang II-treated group. In the Ang II-treated group, the high level of oxidative stress in the aorta was significantly reduced by the AT1 receptor antagonist losartan, the NADPH oxidase inhibitor VAS-2871, the eNOS inhibitor NG-nitro-L-arginine and also to a greater extent by the selective SGLT2 inhibitor empa compared to the dual SGLT1/2 inhibitor sotagliflozin. Conclusion(s) The present findings indicate that although the empa treatment did not affect the hypertensive response of rats to Ang II, the SGLT2 inhibitor prevented the deleterious impact of Ang II on the diastolic cardiac function and remodeling, and the upregulation of eNOS expression and oxidative stress in the aorta wall. Thus, these findings highlight the protective potential of empa on the cardiovascular system in a normoglycemic hypertensive experimental model.
Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH & Co KG (Biberach an der Riss, Germany
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Optical laser triangulation and pulse phase thermography based 3D surface assessment techniques for complex rough surfaces
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