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1.
J Hypertens ; 38(10): 1948-1954, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32890270

RESUMO

OBJECTIVE: Preeclampsia is associated with an elevated risk of cardiovascular disease later in life. Women with a history of preeclampsia are at risk of developing hypertension as well as ischemic heart disease. Identification of women at the highest risk is important to initiate preventive strategies. We investigated whether high-sensitivity cardiac troponin I (hs-cTnI) levels are associated with a history of early-onset preeclampsia, and with hypertension in these high-risk women. METHODS: Approximately 9-10 years after pregnancy, hs-cTnI levels were measured for 339 women of the Preeclampsia Risk Evaluation in FEMales cohort, consisting of 177 women with a history of early-onset preeclampsia and 162 women with a previous uncomplicated index pregnancy. Associations were analyzed using several statistical tests and linear regression analysis. RESULTS: The median hs-cTnI levels (IQR) were 2.50 ng/l (2.30) in women with a history of early-onset preeclampsia and 2.35 ng/l (2.50) in women without a history of preeclampsia, P = 0.53. Among women with a history of early-onset preeclampsia, the hs-cTnI levels were higher in women who were hypertensive compared with their normotensive counterparts (medians 2.60 versus 2.30; P = 0.03). In addition, blood pressure levels increased with increasing hs-cTnI levels. CONCLUSION: We did not find a difference in hs-cTnI levels between women with and without a history of early-onset preeclampsia. Nonetheless, hs-cTnI levels were statistically significantly higher in current hypertensive women with a history of preeclampsia compared with their normotensive counterparts. Therefore, hs-cTnI levels might improve risk prediction for women at the highest risk of cardiovascular disease.

2.
Sci Rep ; 10(1): 14061, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820187

RESUMO

Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage. Lowering blood sugar by the sodium-glucose co-transporter 2 inhibitor empagliflozin provides cardiac protection. We established a new rat model that develops both inducible diabetes and genetic hypertension and investigated the effect of empagliflozin treatment to test the hypothesis if empagliflozin will be protective in a heart failure model which is not based on a primary vascular event. The transgenic Tet29 rat model for inducible diabetes was crossed with the mRen27 hypertensive rat to create a novel model for heart failure with two stressors. The diabetic, hypertensive heart failure rat (mRen27/tetO-shIR) were treated with empagliflozin (10 mg/kg/d) or vehicle for 4 weeks. Cardiovascular alterations were monitored by advanced speckle tracking echocardiography, gene expression analysis and immunohistological staining. The novel model with increased blood pressure und higher blood sugar levels had a reduced survival compared to controls. The rats develop heart failure with reduced ejection fraction. Empagliflozin lowered blood sugar levels compared to vehicle treated animals (182.3 ± 10.4 mg/dl vs. 359.4 ± 35.8 mg/dl) but not blood pressure (135.7 ± 10.3 mmHg vs. 128.2 ± 3.8 mmHg). The cardiac function was improved in all three global strains (global longitudinal strain - 8.5 ± 0.5% vs. - 5.5 ± 0.6%, global radial strain 20.4 ± 2.7% vs. 8.8 ± 1.1%, global circumferential strain - 11.0 ± 0.7% vs. - 7.6 ± 0.8%) and by increased ejection fraction (42.8 ± 4.0% vs. 28.2 ± 3.0%). In addition, infiltration of macrophages was decreased by treatment (22.4 ± 1.7 vs. 32.3 ± 2.3 per field of view), despite mortality was not improved. Empagliflozin showed beneficial effects on cardiovascular dysfunction. In this novel rat model of combined hypertension and diabetes, the improvement in systolic and diastolic function was not secondary to a reduction in left ventricular mass or through modulation of the afterload, since blood pressure was not changed. The mRen27/tetO-shIR strain should provide utility in separating blood sugar from blood pressure-related treatment effects.

3.
J Hypertens ; 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32618885

RESUMO

OBJECTIVE: Preeclampsia is associated with an elevated risk of cardiovascular disease later in life. Women with a history of preeclampsia are at risk of developing hypertension as well as ischemic heart disease. Identification of women at the highest risk is important to initiate preventive strategies. We investigated whether high-sensitivity cardiac troponin I (hs-cTnI) levels are associated with a history of early-onset preeclampsia, and with hypertension in these high-risk women. METHODS: Approximately 9-10 years after pregnancy, hs-cTnI levels were measured for 339 women of the Preeclampsia Risk Evaluation in FEMales cohort, consisting of 177 women with a history of early-onset preeclampsia and 162 women with a previous uncomplicated index pregnancy. Associations were analyzed using several statistical tests and linear regression analysis. RESULTS: The median hs-cTnI levels (IQR) were 2.50 ng/l (2.30) in women with a history of early-onset preeclampsia and 2.35 ng/l (2.50) in women without a history of preeclampsia, P = 0.53. Among women with a history of early-onset preeclampsia, the hs-cTnI levels were higher in women who were hypertensive compared with their normotensive counterparts (medians 2.60 versus 2.30; P = 0.03). In addition, blood pressure levels increased with increasing hs-cTnI levels. CONCLUSION: We did not find a difference in hs-cTnI levels between women with and without a history of early-onset preeclampsia. Nonetheless, hs-cTnI levels were statistically significantly higher in current hypertensive women with a history of preeclampsia compared with their normotensive counterparts. Therefore, hs-cTnI levels might improve risk prediction for women at the highest risk of cardiovascular disease.

4.
Hypertension ; 76(3): 901-909, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32507044

RESUMO

Pregnancy-induced hypertension is a severe pregnancy complication, increasing risk of long-term cardiovascular disease in mothers and offspring. We hypothesized that maternal blood pressure in pregnancy associated with offspring blood pressure; that the associations were sex-specific; and that maternal circulating placental angiogenic markers (PlGF [placental growth factor] and sFlt-1 [soluble fms-like tyrosine kinase-1]) mediated this relationship. We analyzed data from 2434 women and 2217 children from the Odense Child Cohort, a prospective Danish cohort study. Offspring blood pressure trajectory from 4 months to 5 years was highly associated to maternal first, second, and third trimester blood pressure, and mean blood pressure in pregnancy, independent of maternal and offspring covariates. There were offspring sex-specific associations: Girls from mothers in the highest quartile of first and third trimester blood pressure had significantly higher systolic blood pressure at 5 years than the rest of the cohort (mean difference±SEM: 1.81±0.59 and 2.11±0.59 mm Hg, respectively, all P<0.01); whereas boys had significantly higher diastolic blood pressure at 5 years (mean difference±SEM: 1.11±0.45 and 1.03±0.45, respectively, all P<0.05). Concentrations of PlGF at gestational week 28 correlated inversely to maternal gestational blood pressure trajectory, independent of the diagnosis of pregnancy-induced hypertension, adjusted ß coefficients (95% CI) for predicting systolic blood pressure (SBP): -3.18 (-4.66 to -1.70) mm Hg, for predicting diastolic blood pressure (DBP): -2.48 (-3.57 to -1.40) mm Hg. In conclusion, maternal gestational blood pressure predicted offspring blood pressure trajectory until 5 years in a sex-differential manner. Furthermore, subtle alterations in blood pressure in early pregnancy preceded hypertension or preeclampsia, and PlGF was a mediator of cardiovascular health in pregnancy.

7.
Int J Mol Sci ; 21(3)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050556

RESUMO

Several studies have shown that women with a preeclamptic pregnancy exhibit an increased risk of cardiovascular disease. However, the underlying molecular mechanisms are unknown. Animal models are essential to investigate the causes of this increased risk and have the ability to assess possible preventive and therapeutic interventions. Using the latest technologies such as speckle tracking echocardiography (STE), it is feasible to map subclinical changes in cardiac diastolic and systolic function as well as structural changes of the maternal heart. The aim of this work is to compare cardiovascular changes in an established transgenic rat model with preeclampsia-like pregnancies with findings from human preeclamptic pregnancies by STE. The same algorithms were used to evaluate and compare the changes in echoes of human and rodents. Parameters of functionality such as global longitudinal strain (animal -23.54 ± 1.82% vs. -13.79 ± 0.57%, human -20.60 ± 0.47% vs. -15.45 ± 1.55%) as well as indications of morphological changes such as relative wall thickness (animal 0.20 ± 0.01 vs. 0.25 ± 0.01, human 0.34 ± 0.01 vs. 0.40 ± 0.02) are significantly altered in both species after preeclamptic pregnancies. Thus, the described rat model simulates the human situation quite well and is a valuable tool for future investigations regarding cardiovascular changes. STE is a unique technique that can be applied in animal models and humans with a high potential to uncover cardiovascular maladaptation and subtle pathologies.

8.
Hypertension ; 75(1): 202-210, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786987

RESUMO

Preeclampsia is associated with increased cardiovascular long-term risk; however, the underlying functional and structural mechanisms are unknown. We investigated maternal cardiac alterations after preeclampsia. Female rats harboring the human angiotensinogen gene [TGR(hAogen)L1623] develop a preeclamptic phenotype with hypertension and albuminuria during pregnancy when mated with male rats bearing the human renin gene [TGR(hRen)L10J] but behave physiologically normal before and after pregnancy. Furthermore, rats were treated with pravastatin. We tested the hypothesis that statins are a potential therapeutic intervention to reduce cardiovascular alterations due to simulated preeclamptic pregnancy. Although hypertension persists for only 8 days in pregnancy, former preeclampsia rats exhibit significant cardiac hypertrophy 28 days after pregnancy observed in both speckle tracking echocardiography and histological staining. In addition, fibrosis and capillary rarefaction was evident. Pravastatin treatment ameliorated the remodeling and improved cardiac output postpartum. Preeclamptic pregnancy induces irreversible structural changes of cardiac hypertrophy and fibrosis, which can be moderated by pravastatin treatment. This pathological cardiac remodeling might be involved in increased cardiovascular risk in later life.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pravastatina/uso terapêutico , Pré-Eclâmpsia/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Débito Cardíaco/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Período Pós-Parto , Pravastatina/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley
9.
Hypertension ; 74(2): 391-398, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177907

RESUMO

The mineralocorticoid aldosterone increases in plasma in healthy pregnancy along with renin and angiotensin II and plays a key role in the physiological plasma volume expansion. In mice, aldosterone contributes to an optimal fetal development by enhancing PlGF (placental growth factor) expression and trophoblast cell proliferation. In preeclampsia, there is coincident suppression of aldosterone and impaired placental development. We hypothesized that aldosterone independently contributes to placental and birth weight in humans, and high dietary sodium and low potassium intakes affect this relationship adversely. We analyzed 24-hour urine collections and plasma samples from gestational week 29 in a subsample of 569 pregnant women from the Odense Child Cohort-a Danish population-based longitudinal cohort study. Plasma and urinary aldosterone were measured by ELISA, sodium and potassium excretions by flame photometer. Predictive values of aldosterone levels and sodium and potassium intakes were assessed by multiple and Cox regression analyses. Primary outcomes were placental weight and birth weight. Secondary outcome was preeclampsia. Urinary aldosterone excretion at gestational week 29 independently contributed to placental and birth weights (adjusted ß-coefficients [95% CI], 24.50 [9.66-39.35] and 9.59 [4.57-14.61], respectively). Aldosterone levels were not associated to preeclampsia incidence. Salt intake >6 g/d was associated with development of preeclampsia (hazard ratio [95% CI], 5.68 [1.51-21.36]). At gestational week 29, urinary aldosterone excretion is an independent predictor of placental and birth weights. High salt intake is a risk factor for preeclampsia. In perspective, suppression of aldosterone in pregnancy has adverse trophic effects.


Assuntos
Aldosterona/sangue , Potássio/metabolismo , Pré-Eclâmpsia/etiologia , Resultado da Gravidez , Cloreto de Sódio na Dieta/efeitos adversos , Adulto , Estudos de Coortes , Dinamarca , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Incidência , Modelos Lineares , Estudos Longitudinais , Pré-Eclâmpsia/metabolismo , Valor Preditivo dos Testes , Gravidez , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Cloreto de Sódio na Dieta/metabolismo , Estatísticas não Paramétricas
10.
Front Biosci (Landmark Ed) ; 24: 1462-1476, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136991

RESUMO

Preeclampsia is associated with an increased cardiovascular risk later in life. Anti-GPCR autoantibodies have been shown to contribute to the development of cardiovascular disease. We investigated whether anti-GPCR autoantibodies are elevated in women with a history of early-onset preeclampsia 8-11 years postpartum, and whether they correlate with clinical outcomes. We investigated data from the Preeclampsia Risk EValuation in FEMales cohort, a retrospective matched case-control study. Anti AT1R-, beta1AR-, ETAR-, PAR1- and CXCR3- autoantibodies were determined in 485 samples by using commercially available ELISA. Women with the lowest combined levels of autoantibodies and a history of early preeclampsia had significantly higher SBP, DBP and MAP (all p<0.001) compared to the controls. The individual titer levels of autoantibodies were not different between controls and former early PE groups 8-11 years postpartum. In conclusion, regulatory autoantibodies alone are not sufficient to explain hypertension or other cardiovascular pathologic conditions, but together with other risk factors such as a previous hypertensive pregnancy, lower levels of autoantibodies are associated with increased blood pressure.


Assuntos
Autoanticorpos/imunologia , Doenças Cardiovasculares/imunologia , Pré-Eclâmpsia/imunologia , Receptores Acoplados a Proteínas-G/imunologia , Adulto , Autoanticorpos/sangue , Pressão Sanguínea/imunologia , Doenças Cardiovasculares/fisiopatologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Hipertensão/imunologia , Hipertensão/fisiopatologia , Pessoa de Meia-Idade , Pré-Eclâmpsia/fisiopatologia , Gravidez , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
11.
Artigo em Inglês | MEDLINE | ID: mdl-31024453

RESUMO

Intrauterine growth restriction (IUGR) is a condition whereby a fetus is unable to achieve its genetically determined potential size. IUGR is a global health challenge due to high mortality and morbidity amongst affected neonates. It is a multifactorial condition caused by maternal, fetal, placental, and genetic confounders. Babies born of diabetic pregnancies are usually large for gestational age but under certain conditions whereby prolonged uncontrolled hyperglycemia leads to placental dysfunction, the outcome of the pregnancy is an intrauterine growth restricted fetus with clinical features of malnutrition. Placental dysfunction leads to undernutrition and hypoxia, which triggers gene modification in the developing fetus due to fetal adaptation to adverse utero environmental conditions. Thus, in utero gene modification results in future cardiovascular programming in postnatal and adult life. Ongoing research aims to broaden our understanding of the molecular mechanisms and pathological pathways involved in fetal programming due to IUGR. There is a need for the development of effective preventive and therapeutic strategies for the management of growth-restricted infants. Information on the mechanisms involved with in utero epigenetic modification leading to development of cardiovascular disease in adult life will increase our understanding and allow the identification of susceptible individuals as well as the design of targeted prevention strategies. This article aims to systematically review the latest molecular mechanisms involved in the pathogenesis of IUGR in cardiovascular programming. Animal models of IUGR that used nutrient restriction and hypoxia to mimic the clinical conditions in humans of reduced flow of nutrients and oxygen to the fetus will be discussed in terms of cardiac remodeling and epigenetic programming of cardiovascular disease. Experimental evidence of long-term fetal programming due to IUGR will also be included.

12.
Cardiovasc Ultrasound ; 17(1): 7, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010431

RESUMO

Echocardiography is the most commonly applied technique for non-invasive assessment of cardiac function in small animals. Manual tracing of endocardial borders is time consuming and varies with operator experience. Therefore, we aimed to evaluate a novel automated two-dimensional software algorithm (Auto2DE) for small animals and compare it to the standard use of manual 2D-echocardiographic assessment (2DE). We hypothesized that novel Auto2DE will provide rapid and robust data sets, which are in agreement with manually assessed data of animals.2DE and Auto2DE were carried out using a high-resolution imaging-system for small animals. First, validation cohorts of mouse and rat cine loops were used to compare Auto2DE against 2DE. These data were stratified for image quality by a blinded expert in small animal imaging. Second, we evaluated 2DE and Auto2DE in four mouse models and four rat models with different cardiac pathologies.Automated assessment of LV function by 2DE was faster than conventional 2DE analysis and independent of operator experience levels. The accuracy of Auto2DE-assessed data in healthy mice was dependent on cine loop quality, with excellent agreement between Auto2DE and 2DE in cine loops with adequate quality. Auto2DE allowed for valid detection of impaired cardiac function in animal models with pronounced cardiac phenotypes, but yielded poor performance in diabetic animal models independent of image quality.Auto2DE represents a novel automated analysis tool for rapid assessment of LV function, which is suitable for data acquisition in studies with good and very good echocardiographic image quality, but presents systematic problems in specific pathologies.


Assuntos
Algoritmos , Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Disfunção Ventricular Esquerda/diagnóstico , Função Ventricular Esquerda/fisiologia , Animais , Modelos Animais de Doenças , Feminino , Ventrículos do Coração/fisiopatologia , Masculino , Camundongos , Ratos , Ratos Transgênicos , Reprodutibilidade dos Testes , Disfunção Ventricular Esquerda/fisiopatologia
13.
Circulation ; 139(11): 1407-1421, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586752

RESUMO

BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1ß demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças da Aorta/tratamento farmacológico , Arritmias Cardíacas/prevenção & controle , Aterosclerose/tratamento farmacológico , Cardiomegalia/prevenção & controle , Hipertensão/tratamento farmacológico , Propionatos/farmacologia , Angiotensina II , Animais , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/fisiopatologia , Pressão Arterial/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Cardiomegalia/imunologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/imunologia , Hipertensão/fisiopatologia , Masculino , Camundongos Knockout para ApoE , Placa Aterosclerótica , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-29896157

RESUMO

Aim: Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status. Methods: We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant. Results: All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD. Interpretation: Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.

15.
Hypertension ; 71(5): 911-920, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29610268

RESUMO

Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health.


Assuntos
Diabetes Gestacional/genética , Epigênese Genética/genética , Retardo do Crescimento Fetal/genética , Resistência à Insulina/genética , Prenhez , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Animais , Metilação de DNA/genética , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Diabetes Gestacional/fisiopatologia , Feminino , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Hiperinsulinismo/genética , Hiperinsulinismo/fisiopatologia , Imuno-Histoquímica , Gravidez , Ratos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estatísticas não Paramétricas
16.
JCI Insight ; 3(4)2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29467337

RESUMO

Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide-sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.


Assuntos
Arritmias Cardíacas/prevenção & controle , Insuficiência Cardíaca/tratamento farmacológico , Morfolinas/uso terapêutico , Pirimidinas/uso terapêutico , Guanilil Ciclase Solúvel/metabolismo , Administração Oral , Angiotensinogênio/genética , Animais , Arritmias Cardíacas/etiologia , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ecocardiografia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/mortalidade , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Preparação de Coração Isolado , Masculino , Morfolinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Transgênicos , Renina/genética , Volume Sistólico/fisiologia , Taxa de Sobrevida , Resultado do Tratamento
17.
Lab Anim ; 52(5): 479-489, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29426272

RESUMO

Bone protection and metabolism are directly linked to estrogen levels, but exercise is also considered to have bone protective effects. Reduced estrogen levels lead to a variety of disorders, for example, bone loss and reduced movement drive. The objective of this study was to investigate the effects of estrogen on individual voluntary exercise motivation and bone protection. We investigated sham operated, ovariectomized, and ovariectomized with estrogen supplemented Wistar rats (20 weeks old) either with or without access to exercise wheels. We selected an experimental approach where we could monitor the individual exercise of group-housed rats with ad libitum access to a running wheel with the help of a subcutaneous chip. In vivo and ex vivo microcomputed tomography analyses of the tibia were performed at two-week intervals from week 0 to week 6. Furthermore, tibial trabecular structure was evaluated based on histomorphometric analyses. We observed a significant bone protective effect of E2. For exercise performance, a substantially high intra-group variability was observed, especially in the E2 group. We presume that dominant behavior occurs within the group-housed rats resulting in a hierarchical access to the running wheel and a high variability of distance run. Exercise did not prevent ovariectomy-induced bone loss. However, lack of estrogen within the ovariectomized rats led to a drastically reduced activity prevented by estrogen supplementation. Our findings are important for future studies working with group-housed rats and exercise. The reason for the high intra-group variability in exercise needs to be investigated in future studies.


Assuntos
Estrogênios/administração & dosagem , Exercício Físico/psicologia , Motivação , Osteoporose/fisiopatologia , Tíbia/fisiologia , Animais , Exercício Físico/fisiologia , Feminino , Humanos , Modelos Animais , Ovariectomia , Condicionamento Físico Animal/fisiologia , Ratos , Ratos Wistar , Microtomografia por Raio-X
18.
Mol Cell Endocrinol ; 392(1-2): 125-35, 2014 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-24859648

RESUMO

8-Prenylnaringenin (8-PN) and naringenin (Nar) are phytoestrogens found in food items and nutritional supplements, while 6-(1.1-dimethylallyl)naringenin (6-DMAN) is a component of an African plant. Besides their assumed beneficial effects they may promote mammary and endometrial cancer. We therefore assessed their proliferative and estrogenic potential on the mammary gland in vitro and in vivo. In competitive estrogen receptor (ER) ligand binding assays 8-PN displayed a high relative binding affinity for both ERs with a preference for ERα and had the strongest mitotic effect on MCF-7 cells among the test substances. In a three day exposure in young adult ovariectomized female rats 15 mg/kg 8-PN had the highest capacity to increase the number of terminal end buds (TEB) in the mammary gland and stimulated expression of proliferation markers in epithelial ductal cells, followed by 6-DMAN and Nar, but overall their capacity to stimulate proliferation was weak in comparison to 17ß-Estradiol (E2).


Assuntos
Flavanonas/farmacologia , Glândulas Mamárias Animais/citologia , Anfirregulina/metabolismo , Animais , Caseínas/metabolismo , Contagem de Células , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Flavanonas/administração & dosagem , Flavanonas/química , Flavanonas/metabolismo , Humanos , Concentração Inibidora 50 , Antígeno Ki-67/metabolismo , Células MCF-7 , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Endogâmicos Lew , Receptores de Progesterona/metabolismo
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