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1.
BMC Cardiovasc Disord ; 20(1): 51, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013884

RESUMO

BACKGROUND: Aortic valve regurgitation (AR) results in left ventricle (LV) volume overload (VO) leading to its dilation and hypertrophy (H). We study a rat model of severe AR induced by puncturing one or two leaflets using a catheter. Most of our studies were conducted in male animals. Recently, we started investigating if sex dimorphism existed in the AR rat model. We observed that AR females developed as much LVH as males but morphological remodeling differences were present. A head-to-head comparison of LV morphological and functional changes had never been performed in AR males (M) and females (F) using the latest modalities in cardiac imaging by echocardiography. METHODS: We performed a longitudinal study to evaluate the development of LV hypertrophy caused by chronic AR in male and female rats over 6 months. Sham-operated (sham) animals were used as controls. RESULTS: LV diastolic volumes (EDV) increased more over 6 months in sham males than in females (38% vs. 23% for EDV, both p < 0.01). AR resulted in significant LV dilation for both sexes (54% vs. 51% increase in EDV) vs. baseline values. Since normal cardiac growth was less in females, dilation from AR was relatively more important for them (88% (M) vs. 157% (F) increase in EDV over sham). AR caused LV wall thickening in both males and females. It happened sooner for AR females and was more important than in males (25% (M) vs. 56% (F) increase in septum thickness at 2 months and 10% (M) vs. 30% (F) at 6 months). We then evaluated if AR was associated with changes in LV strain using speckle-tracking 2D echocardiography. Global longitudinal strain remained similar between AR and sham animals. Circumferential strain was negatively modulated by AR but only in females and early after VO induction (13% (M) vs. 26% (F)). CONCLUSION: AR resulted in more LV dilation and quicker wall thickening in female AR rats compared to males. Global circumferential strain was negatively modulated in AR females but not in males. AR also seemed to lead to a more spherical LV shape in females whereas; it kept mostly an ellipsoid shape in males. This can influence validity of mass estimation of the dilated LV in females by echocardiography.


Assuntos
Insuficiência da Valva Aórtica/complicações , Hipertrofia Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Ratos Wistar , Índice de Gravidade de Doença , Caracteres Sexuais , Fatores Sexuais , Fatores de Tempo
2.
J Heart Valve Dis ; 26(3): 281-289, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-29092112

RESUMO

BACKGROUND AND AIM OF THE STUDY: Mitral leaflet enlargement in patients with chronic aortic regurgitation (AR) has been identified as an adaptive mechanism potentially able to prevent functional mitral regurgitation (FMR) in response to left ventricular (LV) dilatation. The timing of valve enlargement is not known, and the related mechanisms are largely unexplored. METHODS: AR was induced in 58 rats, and another 54 were used as sham controls. Animals were euthanized at different time points after AR creation (48 h, one week, and three months), and AR severity, FMR and LV dilatation were assessed using echocardiography. Mitral valves were harvested to document the reactivation of embryonic growth pathways. RESULTS: AR animals had increased LV dimensions and mitral annulus size. No animal developed FMR. No change in leaflet length or thickness was seen at 48 h; however, anterior mitral leaflets were longer and thicker in AR animals at one week and three months. Molecular changes were present early (at 48 h and at one week), with positive staining for transforming growth factor-b1 (TGF-b1), Alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2), which suggested active matrix remodeling. Increased gene expression for collagen 1, TGF-ß1, α-SMA and MMP-2 was found in the mitral valve at 48 h and at one week, but after three months their expression had returned to normal. CONCLUSIONS: This model of AR induces active expansion and thickening of the mitral leaflets. Growth signals are expressed acutely, but not at three months, which suggests that most of this enlargement occurs at an early stage. The stimulation of valvular growth could represent a new strategy for the prevention of FMR.


Assuntos
Insuficiência da Valva Aórtica/patologia , Proliferação de Células , Matriz Extracelular/patologia , Valva Mitral/patologia , Actinas/genética , Actinas/metabolismo , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/metabolismo , Insuficiência da Valva Aórtica/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia Doppler , Matriz Extracelular/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Valva Mitral/diagnóstico por imagem , Valva Mitral/metabolismo , Valva Mitral/fisiopatologia , Ratos Wistar , Fatores de Tempo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima , Função Ventricular Esquerda , Remodelação Ventricular
3.
BMC Cardiovasc Disord ; 14: 123, 2014 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-25249193

RESUMO

BACKGROUND: The composition of a diet can influence myocardial metabolism and development of left ventricular hypertrophy (LVH). The impact of a high-fat diet in chronic left ventricular volume overload (VO) causing eccentric LVH is unknown. This study examined the effects of chronic ingestion of a high-fat diet in rats with chronic VO caused by severe aortic valve regurgitation (AR) on LVH, function and on myocardial energetics and survival. METHODS: Male Wistar rats were divided in four groups: Shams on control or high-fat (HF) diet (15 rats/group) and AR rats fed with the same diets (ARC (n = 56) and ARHF (n = 32)). HF diet was started one week before AR induction and the protocol was stopped 30 weeks later. RESULTS: As expected, AR caused significant LV dilation and hypertrophy and this was exacerbated in the ARHF group. Moreover, survival in the ARHF group was significantly decreased compared the ARC group. Although the sham animals on HF also developed significant obesity compared to those on control diet, this was not associated with heart hypertrophy. The HF diet in AR rats partially countered the expected shift in myocardial energy substrate preference usually observed in heart hypertrophy (from fatty acids towards glucose). Systolic function was decreased in AR rats but HF diet had no impact on this parameter. The response to HF diet of different fatty acid oxidation markers as well as the increase in glucose transporter-4 translocation to the plasma membrane compared to ARC was blunted in AR animals compared to those on control diet. CONCLUSIONS: HF diet for 30 weeks decreased survival of AR rats and worsened eccentric hypertrophy without affecting systolic function. The expected adaptation of myocardial energetics to volume-overload left ventricle hypertrophy in AR animals seemed to be impaired by the high-fat diet suggesting less metabolic flexibility.


Assuntos
Insuficiência da Valva Aórtica/complicações , Dieta Hiperlipídica/efeitos adversos , Hipertrofia Ventricular Esquerda/etiologia , Obesidade/complicações , Adaptação Fisiológica , Animais , Insuficiência da Valva Aórtica/diagnóstico , Insuficiência da Valva Aórtica/metabolismo , Insuficiência da Valva Aórtica/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Ácidos Graxos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Oxirredução , Ratos Wistar , Fatores de Risco , Fatores de Tempo , Função Ventricular Esquerda
4.
BMC Cardiovasc Disord ; 14: 190, 2014 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-25518920

RESUMO

BACKGROUND: Patients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR. METHODS: LV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months. RESULTS: MicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them. CONCLUSION: This study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Insuficiência da Valva Aórtica/metabolismo , Metabolismo Energético/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Condicionamento Físico Animal , Resistência Física , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Modelos Animais de Doenças , Regulação para Baixo , Glucose/metabolismo , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Masculino , Miocárdio/metabolismo , Ratos Wistar , Ultrassonografia
5.
Am J Physiol Heart Circ Physiol ; 300(1): H125-34, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20971767

RESUMO

The development of left ventricular (LV) hypertrophy (LVH) can be affected by diet manipulation. Concentric LVH resulting from pressure overload can be worsened by feeding rats with a high-fructose diet. Eccentric LVH is a different type of hypertrophy and is associated with volume overload (VO) diseases. The impact of an abnormal diet on the development of eccentric LVH and on ventricular function in chronic VO is unknown. This study therefore examined the effects of a fructose-rich diet on LV eccentric hypertrophy, ventricular function, and myocardial metabolic enzymes in rats with chronic VO caused by severe aortic valve regurgitation (AR). Wistar rats were divided in four groups: sham-operated on control diet (SC; n = 13) or fructose-rich diet (SF; n = 13) and severe aortic regurgitation fed with the same diets [aortic regurgitation on control diet (ARC), n = 16, and aortic regurgitation on fructose-rich diet (ARF), n = 13]. Fructose-rich diet was started 1 wk before surgery, and the animals were euthanized 9 wk later. SF and ARF had high circulating triglycerides. ARC and ARF developed significant LV eccentric hypertrophy after 8 wk as expected. However, ARF developed more LVH than ARC. LV ejection fraction was slightly lower in the ARF compared with ARC. The increased LVH and decreased ejection fraction could not be explained by differences in hemodynamic load. SF, ARC, and ARF had lower phosphorylation levels of the AMP kinase compared with SC. A fructose-rich diet worsened LV eccentric hypertrophy and decreased LV function in a model of chronic VO caused by AR in rats. Normal animals fed the same diet did not develop these abnormalities. Hypertriglyceridemia may play a central role in this phenomenon as well as AMP kinase activity.


Assuntos
Carboidratos da Dieta/efeitos adversos , Frutose/administração & dosagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Análise de Variância , Animais , Insuficiência da Valva Aórtica/metabolismo , Insuficiência da Valva Aórtica/fisiopatologia , Western Blotting , Carboidratos da Dieta/metabolismo , Frutose/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Volume Sistólico , Triglicerídeos/sangue
6.
J Am Coll Cardiol ; 75(4): 395-405, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32000951

RESUMO

BACKGROUND: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves. OBJECTIVES: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves. METHODS: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves. RESULTS: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm2 vs. 15.1 ± 1.6 cm2, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group. CONCLUSIONS: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.


Assuntos
Insuficiência da Valva Mitral/fisiopatologia , Valva Mitral/diagnóstico por imagem , Infarto do Miocárdio/complicações , Remodelação Ventricular , Animais , Insuficiência da Valva Aórtica/complicações , Ecocardiografia Tridimensional , Matriz Extracelular/metabolismo , Feminino , Fibrose , Imageamento por Ressonância Magnética , Masculino , Isquemia Miocárdica/complicações , Ovinos , Tomografia Computadorizada por Raios X , Valva Tricúspide/diagnóstico por imagem
7.
J Heart Valve Dis ; 18(4): 421-8, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19852147

RESUMO

BACKGROUND AND AIM OF THE STUDY: The calcification of cardiac valves is more frequently observed on left-sided (aortic or mitral) than right-sided (pulmonic or tricuspid) valves. The cause of this preferential left-sided calcification remains relatively unknown. The study aim was to evaluate the capacity of interstitial cells isolated from the four cardiac valves of healthy adult pigs to calcify in culture. METHODS: Interstitial cells were isolated from the valve leaflets of three healthy young pigs and cultured in DMEM/fetal bovine serum (10%) in the presence or absence of osteogenic additives (ascorbic acid, dexamethasone, beta-glycerophosphate). RESULTS: The proliferation rate was similar for cells from each of the four valves. After longer periods of culture (> 10 days), cells from each valve spontaneously formed several calcification nodules, the process being accelerated in the presence of osteogenic additives (to 4-7 days). Alkaline phosphatase (AP) activity was highest in cells originating from the aortic and mitral valves, respectively, and least in those from the pulmonic and tricuspid valves. Culture with the osteogenic additives increased the AP activity by at least 50% for each valve, but the relative AP activity between cells from each valve origin tended to remain similar (aortic > mitral > pulmonic > tricuspid). Interestingly, the levels of matrix Gla-protein mRNA (an endogenous calcification inhibitor) followed an opposite trend of expression for each valve. CONCLUSION: Interstitial cells from porcine cardiac valves share similarities, although the capacity to calcify is more evident in cells from valves of the left side of the heart. Interstitial cells from the aortic valve displayed the greatest potential for calcification.


Assuntos
Calcinose/patologia , Células do Tecido Conjuntivo/patologia , Valvas Cardíacas/patologia , Fosfatase Alcalina/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Células do Tecido Conjuntivo/metabolismo , Valvas Cardíacas/metabolismo , Suínos
8.
PeerJ ; 7: e7461, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31404429

RESUMO

Background. Men and women differ in their susceptibility to cardiovascular disease, though the underlying mechanism has remained elusive. Heart disease symptoms, evolution and response to treatment are often sex-specific. This has been studied in animal models of hypertension or myocardial infarction in the past but has received less attention in the context of heart valve regurgitation. The aim of the study was to evaluate the development of cardiac hypertrophy (CH) in response to left ventricle (LV) volume overload (VO) caused by chronic aortic valve regurgitation (AR) in male and female rats treated or not with angiotensin II receptor blocker (ARB), valsartan. We studied eight groups of Wistar rats: male or female, AR or sham-operated (sham) and treated or not with valsartan (30 mg/kg/day) for 9 weeks starting one week before AR surgical induction. Results. As expected, VO from AR resulted for both male and female rats in significant LV dilation (39% vs. 40% end-diastolic LV diameter increase, respectively; p < 0.0001) and CH (53% vs. 64% heart weight increase, respectively; p < 0.0001) compared to sham. Sex differences were observed in LV wall thickening in response to VO. In untreated AR males, relative LV wall thickness (a ratio of wall thickness to end-diastolic diameter) was reduced compared to sham, whereas this ratio in females remained unchanged. ARB treatment did not prevent LV dilation in both male and female animals but reversed LV wall thickening in females. Systolic and diastolic functions in AR animals were altered similarly for both sexes. ARB treatment did not improve systolic function but helped normalizing diastolic parameters such as left atrial mass and E wave slope in female AR rats. Increased LV gene expression of Anp and Bnp was normalized by ARB treatment in AR females but not in males. Other hypertrophy gene markers (Fos, Trpc6, Klf15, Myh6 and Myh7) were not modulated by ARB treatment. The same was true for genes related to LV extracellular matrix remodeling (Col1a1, Col3a1, Fn1, Mmp2, Timp1 and Lox). In summary, ARB treatment of rats with severe AR blocked the female-specific hypertrophic response characterized by LV chamber wall thickening. LV dilation, on the other hand, was not significantly decreased by ARB treatment. This also indicates that activation of the angiotensin II receptor is probably more involved in the early steps of LV remodeling caused by AR in females than in males.

9.
PeerJ ; 7: e7924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31656705

RESUMO

Aortic valve regurgitation (AR) can result in heart failure from chronic overloading of the left ventricle (LV). Little is known of the role of estrogens in the LV responses to this condition. The aim of the study was to compare LV remodeling in female rats with severe AR in absence of estrogens by ovariectomy (Ovx). In a first study, we investigated over 6 months the development of hypertrophy in four groups of female Wistar rats: AR or sham-operated (sham) and Ovx or not. Ovx reduced normal heart growth. As expected, volume overload (VO) from AR resulted in significant LV dilation (42% and 32% increase LV end-diastolic diameter in intact and Ovx groups vs. their respective sham group; p < 0.0001). LV weight was also significantly and similarly increased in both AR groups (non-Ovx and Ovx). Increase in stroke volume or cardiac output and loss of systolic function were similar between AR intact and AR Ovx groups compared to sham. We then investigated what were the effects of 17beta-estradiol (E2; 0.03 mg/kg/day) treatment on the parameters studied in Ovx rats. Ovx reduced uterus weight by 85% and E2 treatment restored up to 65% of the normal weight. E2 also helped normalize heart size to normal values. On the other hand, it did not influence the extent of the hypertrophic response to AR. In fact, E2 treatment further reduced LV hypertrophy in AR Ovx rats (41% over Sham Ovx + E2). Systolic and diastolic functions parameters in AR Ovx + E2 were similar to intact AR animals. Ovx in sham rats had a significant effect on the LV gene expression of several hypertrophy markers. Atrial natriuretic peptide (Nppa) gene expression was reduced by Ovx in sham-operated females whereas brain natriuretic peptide (Nppb) expression was increased. Alpha (Myh6) and beta (Myh7) myosin heavy chain genes were also significantly modulated by Ovx in sham females. In AR rats, LV expression of both Nppa and Nppb genes were increased as expected. Ovx further increased it of AR rats for Nppa and did the opposite for Nppb. Interestingly, AR in Ovx rats had only minimal effects on Myh6 and Myh7 genes whereas they were modulated as expected for intact AR animals. In summary, loss of estrogens by Ovx in AR rats was not accompanied by a worsening of hypertrophy or cardiac function. Normal cardiac growth was reduced by Ovx in sham females but not the hypertrophic response to AR. On the other hand, Ovx had important effects on LV gene expression both in sham and AR female rats.

10.
Physiol Rep ; 7(9): e14088, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31054220

RESUMO

The aim of the study was to characterize if the development of cardiac hypertrophy (CH) caused by severe left ventricle (LV) volume overload (VO) from chronic aortic valve regurgitation (AR) in male rats was influenced by androgens. We studied Wistar rats with/without orchiectomy (Ocx) either sham-operated (S) or with severe AR for 26 weeks. Loss of testosterone induced by Ocx decreased general body growth. Cardiac hypertrophy resulting from AR was relatively more important in intact (non-Ocx) animals than in Ocx ones compared to their respective S group (60% vs. 40%; P = 0.019). The intact AR group had more LV dilation, end-diastolic LV diameter being increased by 37% over S group and by 17% in AROcx rats (P < 0.0001). Fractional shortening (an index of systolic function) decreased only by 15% in AROcx compared to 26% for intact AR animals (P = 0.029). Changes in LV gene expression resulting from CH were more marked in intact rats than in AROcx animals, especially for genes linked to extracellular matrix remodeling and energy metabolism. The ratio of hydroxyacyl-Coenzyme A dehydrogenase activity over hexokinase activity, an index of the shift of myocardial substrate use toward glucose from the preferred fatty acids, was significantly decreased in the AR group but not in AROcx. Finally, pJnk2 LV protein content was more abundant in AR than in AROcx rats, indicating decreased activation of this stress pathway in the absence of androgens. In summary, testosterone deficiency in rats with severe LV VO resulted in less CH and a normalization of the LV gene expression profile.


Assuntos
Cardiomegalia/prevenção & controle , Testosterona/deficiência , Animais , Insuficiência da Valva Aórtica/complicações , Biomarcadores/metabolismo , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Metabolismo Energético/fisiologia , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/fisiologia , Ventrículos do Coração/metabolismo , Hemodinâmica/fisiologia , Masculino , Orquiectomia , Ratos Wistar , Transdução de Sinais/fisiologia , Testosterona/fisiologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia
11.
Life Sci ; 82(5-6): 265-72, 2008 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-18155733

RESUMO

The early events leading to the establishment of left ventricular hypertrophy associated to pressure overload (PO) are not well characterized. To explore these early events, aortic banding (AB) was performed in rats to induce left ventricle (LV) PO. Animals were sacrificed after 24, 48 h or 14 days. An echocardiogram was performed before the procedure and at sacrifice. LVs were preserved for the evaluation of fibrosis, angiotensin II (AT) receptors expression and stress-related MAP kinases (ERK 1/2, JNK and p38) pathways. We observed that concentric LV hypertrophy was established after only 14 days. Collagen I and fibronectin gene expressions were decreased the first 2 days after AB induction whereas AT receptors mRNA levels were sharply increased. ERK 1/2 and JNK activities in LV homogenates were decreased 24 h after AB but came back to normal after 14 days. p38 activity however was stable during the period studied. We also evaluated the presence of two phosphorylated transcription factors related to JNK signaling pathway (ATF-2 and c-Jun) in cardiomyocyte nuclei. The proportion of LV cell nuclei positive for these two activated transcription factors was significantly reduced in AB rats compared to sham. These results suggest that the early response of the LV to acute PO is to attenuate the expression of some pro-fibrotic and pro-hypertrophic signaling pathways and possibly AT signaling by decreasing ERK 1/2 and JNK relative activities.


Assuntos
Estenose da Valva Aórtica/metabolismo , Pressão Sanguínea , Hipertrofia Ventricular Esquerda/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Miócitos Cardíacos/metabolismo , Remodelação Ventricular , Animais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/fisiopatologia , Núcleo Celular/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Expressão Gênica , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Ratos , Ratos Wistar , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo
12.
J Heart Valve Dis ; 17(4): 381-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18751467

RESUMO

BACKGROUND AND AIM OF THE STUDY: Aortic valve sclerosis is fairly common and is currently seen as a marker of systemic atherosclerosis. For unclear reasons only a minority of those sclerotic valves will evolve to become stenotic suggesting that atherogenic factors alone are insufficient to explain the development of valve stenosis. We had reported in a model of cholesterol fed rabbits that a combination of high cholesterol with vitamin D supplementation was necessary to induce valve stenosis and significant calcium deposition whereas high cholesterol alone only induced a sclerosis of the valve. In this study, we further evaluated the role of vitamin D treatment in the development of aortic valve disease (sclerosis or stenosis) in this rabbit model. METHODS: Rabbits were divided in 4 groups followed for 12 weeks: 1) no treatment; 2) cholesterol-enriched diet, 3) cholesterol-enriched diet + vitamin D2 (VD; 50000IU, daily) 4) VD alone for 12 weeks. Echocardiographic assessment of the aortic valve was done at baseline, and every 4 weeks thereafter. Aortic valve area, maximal and mean transvalvular gradients were recorded and compared over time. Immunohistological study of the valves of AS rabbits was also realized for several classical atherosclerosis markers. RESULTS: Vitamin D2 treated animal did not develop any stenosis of the valve despite increased echogenicity due to diffuse calcium deposits on the leaflets without any atherosclerotic lesions. Only the combination of high cholesterol with VD resulted in a decrease of aortic valve area. Immunohistological analysis of aortic valves from VD rabbits showed the presence of calcium deposits, T-cell infiltration in addition to positive labeling for alpha-smooth muscle cell actin. We did not observe macrophage infiltration in aortic valve leaflets of VD rabbits. CONCLUSION: Hypercholesterolemia or vitamin D supplements alone could not induce aortic valve stenosis in our animal model whereas the combination resulted in a decreased aortic valve area. These findings support the hypothesis that a combination of atherosclerotic and calcifying factors is necessary to induce aortic valve stenosis in this model.


Assuntos
Estenose da Valva Aórtica/etiologia , Cálcio/sangue , Colesterol na Dieta/efeitos adversos , Ergocalciferóis/efeitos adversos , Hipercolesterolemia/complicações , Animais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/diagnóstico , Modelos Animais de Doenças , Ecocardiografia , Masculino , Fosfatos/sangue , Coelhos , Esclerose
13.
J Heart Valve Dis ; 17(3): 300-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18592927

RESUMO

BACKGROUND AND AIM OF THE STUDY: Chronic aortic regurgitation (AR) induces left ventricular (LV) hypertrophy and eventually LV dysfunction. While the effects of chronic AR on the left ventricle are well known, the effects of acute AR have not been adequately evaluated. It was hypothesized that the LV tissues would be rapidly remodeled by acute AR, and that the renin-angiotensin system would be involved in that acute remodeling. METHOD: The early LV adaptations to acute AR were evaluated serially over a period of 14 days, using a rat model. Adaptations were evaluated in vivo by echocardiography, and in vitro on explanted heart tissue after one, two, or 14 days. RESULTS: After 14 days, the left ventricle of AR rats was already significantly hypertrophied and dilated (end-diastolic diameter +16% (p <0.05) versus sham; LV mass +16% (p <0.01) versus sham). A short and transient increase in fractional shortening was observed during the first 48 h after AR induction. The cardiomyocyte cross-sectional area and perivascular fibrosis were significantly increased after 14 days of AR. The number of fibronectin-positive cells in LV sections rapidly increased, as did the fibronectin protein and mRNA content of LV crude homogenates. The expression of pro-matrix metalloproteinase 2 was clearly abnormal after two days. Significant shifts in the expression of angiotensin II receptors were also detected as early as one 1 day. CONCLUSION: Significant macroscopic and microscopic abnormalities were present in the left ventricle of rats with acute AR, soon after its induction. Considerable hypertrophy, perivascular fibrosis and extracellular matrix (ECM) remodeling were present after only 14 days. These results suggest that, in AR, the myocytes and ECM are affected significantly at a very early stage of the disease.


Assuntos
Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/fisiopatologia , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Remodelação Ventricular , Doença Aguda , Animais , Insuficiência da Valva Aórtica/metabolismo , Pressão Sanguínea/fisiologia , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Frequência Cardíaca/fisiologia , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Wistar , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Fator de Transcrição STAT3/metabolismo
14.
FEBS Open Bio ; 8(10): 1624-1635, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30338214

RESUMO

Cardiac hypertrophy (CH) is an important and independent predictor of morbidity and mortality. Through expression profiling, we recently identified a subset of genes (Dhrs7c, Decr, Dhrs11, Dhrs4, Hsd11b1, Hsd17b10, Hsd17b8, Blvrb, Pecr), all of which are members of the short-chain dehydrogenase/reductase (SDR) superfamily and are highly expressed in the heart, that were significantly dysregulated in a rat model of CH caused by severe aortic valve regurgitation (AR). Here, we studied their expression in various models of CH, as well as factors influencing their regulation. Among the nine SDR genes studied, all but Hsd11b1 were down-regulated in CH models (AR rats or mice infused with either isoproterenol or angiotensin II). This regulation showed a clear sex dimorphism, being more evident in males than in females irrespective of CH levels. In neonatal rat cardiomyocytes, we observed that treatment with the α1-adrenergic receptor agonist phenylephrine mostly reproduced the observations made in CH animals models. Retinoic acid, on the other hand, stimulated the expression of most of the SDR genes studied, suggesting that their expression may be related to cardiomyocyte differentiation. Indeed, levels of expression were found to be higher in the hearts of adult animals than in neonatal cardiomyocytes. In conclusion, we identified a group of genes modulated in animal models of CH and mostly in males. This could be related to the activation of the fetal gene expression program in pathological CH situations, in which these highly expressed genes are down-regulated in the adult heart.

15.
Diabetes ; 67(7): 1285-1296, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29496744

RESUMO

The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Recent studies have demonstrated that the etiology of obesity-related insulin resistance that develops with aging differs from that induced by high-calorie diets. Whereas the role of adaptive immunity in changes in energy metabolism driven by nutritional challenges has recently gained attention, its impact on aging remains mostly unknown. Here we found that the number of follicular B2 lymphocytes and expression of the B-cell-specific transcriptional coactivator OcaB increase with age in spleen and in intra-abdominal epididymal white adipose tissue (eWAT), concomitantly with higher circulating levels of IgG and impaired glucose homeostasis. Reduction of B-cell maturation and Ig production-especially that of IgG2c-by ablation of OcaB prevented age-induced glucose intolerance and insulin resistance and promoted energy expenditure by stimulating fatty acid utilization in eWAT and brown adipose tissue. Transfer of wild-type bone marrow in OcaB-/- mice replenished the eWAT B2-cell population and IgG levels, which diminished glucose tolerance, insulin sensitivity, and energy expenditure while increasing body weight gain in aged mice. Thus these findings demonstrate that upon aging, modifications in B-cell-driven adaptive immunity contribute to glucose intolerance and fat accretion.


Assuntos
Envelhecimento/metabolismo , Linfócitos B/fisiologia , Metabolismo Energético/genética , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Obesidade , Transativadores/genética , Adolescente , Adulto , Idoso , Envelhecimento/genética , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Epididimo , Feminino , Intolerância à Glucose/genética , Intolerância à Glucose/imunologia , Intolerância à Glucose/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Obesidade/imunologia , Obesidade/metabolismo , Adulto Jovem
16.
Sci Rep ; 7(1): 729, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28389667

RESUMO

Aortic valve regurgitation (AR) imposes a volume overload (VO) to the left ventricle (LV). Male rats with a pathological heart overload usually progress more quickly towards heart failure than females. We examined whether a sexual dimorphism exists in the myocardial transcriptional adaptations to AR. Adult Wistar male and female rats either underwent a sham operation or were induced with AR and then followed for 26 weeks. Female AR rats gained relatively more LV mass than males (75 vs. 42%). They had a similar increase in LV chamber dimensions compared to males but more wall thickening. On the other hand, fatty acid oxidation (FAO)-related LV enzyme activity was only decreased in AR males. The expression of genes encoding FAO-related enzymes was only reduced in AR males and not in females. A similar situation was observed for the expression of genes involved in mitochondrial biogenesis or function as well as for genes encoding for transcription factors implicated in the control of bioenergetics and mitochondrial function (Errα, Errγ or Pgc1α). Although females develop more LV hypertrophy from severe VO, their myocardial gene expression remains closer to normal. This could provide survival benefits for females with severe VO.


Assuntos
Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Transcrição Gênica , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Biomarcadores , Biópsia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/patologia , Modelos Animais de Doenças , Ecocardiografia , Metabolismo Energético , Feminino , Testes de Função Cardíaca , Hemodinâmica , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Masculino , Mitocôndrias Cardíacas/metabolismo , Ratos , Fatores Sexuais , Remodelação Ventricular
17.
Am J Hypertens ; 19(8): 843-50, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16876685

RESUMO

BACKGROUND: Hypertension (HT) and aortic valve regurgitation (AR) often coexist but the specific impacts of AR + HT on the left ventricle (LV) are still unknown. The best treatment strategy for this combination of diseases is also unclear. The objectives of this study were 1) to evaluate LV function, remodeling and 2) to assess the effects of the angiotensin-converting enzyme (ACE) inhibitor captopril (C) in rats with AR +/- HT in spontaneously hypertensive rats (SHR). METHODS: Animals were grouped as follows: normotensive (NT) Wistar-Kyoto, NT + AR, hypertensive SHR (HT), and HT + AR receiving or not captopril (150 mg/kg/d). Hearts were evaluated in vivo by echocardiography and harvested for tissue analysis after 6 months of evolution. RESULTS: The HT + AR rats had the worst LV hypertrophy (LVH), subendocardial fibrosis, and lowest ejection fraction. Captopril normalized BP in HT and HT + AR, but could not prevent LVH in HT + AR as well as it did in isolated HT. The LV ejection fraction remained below normal in HT + AR + captopril compared to HT alone + captopril. Cardiomyocyte hypertrophy remained in HT + AR + captopril but was normalized in HT + captopril. Subendocardial fibrosis was reduced by captopril in HT + AR. CONCLUSIONS: The AR + HT rats had the most severe myocardial abnormalities. High dose captopril was effective to slow LVH and preserve normal LV ejection fraction in isolated HT or AR, but was less effective when both pathologies were combined. Prohypertrophic stimuli clearly remain active in HT + AR despite ACE inhibition. These results suggest that a very aggressive medical treatment strategy may be required to optimize LV protection when AR and HT co-exist.


Assuntos
Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/tratamento farmacológico , Modelos Animais de Doenças , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Animais , Insuficiência da Valva Aórtica/patologia , Insuficiência da Valva Aórtica/fisiopatologia , Captopril/uso terapêutico , Fibrose Endomiocárdica/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertrofia/fisiopatologia , Masculino , Tamanho do Órgão , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos WKY
18.
J Heart Valve Dis ; 15(3): 345-51, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16784070

RESUMO

BACKGROUND AND AIM OF THE STUDY: Aortic valve regurgitation (AR) can result in heart failure from chronic overloading of the left ventricle. As little is known of gender-specific responses of the left ventricle to this condition, the study aim was to compare left ventricular (LV) remodeling in male and female rats with severe AR. In order to assess the impact of estrogens on LV remodeling in AR, the effect of ovariectomy (OVX) was also evaluated. METHODS: AR was created in adult Wistar rats (females (control or OVX) and males). Animals were followed for 26 weeks and compared to sham-operated groups. Heart function was evaluated in vivo using echocardiography, and the hearts were subsequently harvested for tissue analysis. RESULTS: The LV ejection fraction was decreased similarly in both sexes. Despite similar echocardiographic AR severity, females had higher indexed cardiac output and the largest increase in LV weight, cardiomyocyte hypertrophy and eccentric remodeling. No differences were observed between control and OVX females. Ovariectomy had no significant impact on any of the parameters monitored. CONCLUSION: Female rats developed more LV remodeling in response to chronic AR than males. AR appears to impose a greater LV workload on females due to their smaller body and heart size. Hormonal status did not have any impact on LV remodeling in this experimental model.


Assuntos
Insuficiência da Valva Aórtica/fisiopatologia , Remodelação Ventricular , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Colágeno/genética , Modelos Animais de Doenças , Ecocardiografia , Feminino , Fibronectinas/genética , Masculino , Tamanho do Órgão , Ovariectomia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Caracteres Sexuais
19.
PLoS One ; 11(5): e0154398, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27166674

RESUMO

Inactivation of Kcc3 in a mixed 129/Sv×C57BL/6 mouse background has been previously found to increase systemic blood pressure (BP) through presumed neurogenic mechanisms. Yet, while this background is generally not considered ideal to investigate the cardiovascular system, KCC3 is also expressed in the arterial wall and proximal nephron. In the current study, the effects of Kcc3 ablation was investigated in a pure rather than mixed C57BL/6J background under regular- and high-salt diets to determine whether they could be mediated through vasculogenic and nephrogenic mechanisms. Aortas were also assessed for reactivity to pharmacological agents while isolated from the influence of sympathetic ganglia. This approach led to the identification of unforeseen abnormalities such as lower pulse pressure, heart rate, aortic reactivity and aortic wall thickness, but higher diastolic BP, left ventricular mass and urinary output in the absence of increased catecholamine levels. Salt loading also led systolic BP to be higher, but to no further changes in hemodynamic parameters. Importantly, aortic vascular smooth muscle cells and cardiomyocytes were both found to express KCC3 abundantly in heterozygous mice. Hence, Kcc3 inactivation in our model caused systemic vascular resistance and ventricular mass to increase while preventing extracellular fluid volume to accumulate. Given that it also affected the physiological properties of aortas in vitro, vasculogenic mechanisms could therefore account for a number of the hemodynamic abnormalities observed.


Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/metabolismo , Deleção de Genes , Osmose , Poliúria/complicações , Poliúria/metabolismo , Simportadores/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Pressão Sanguínea , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/fisiopatologia , Coração/fisiopatologia , Testes de Função Cardíaca , Hemodinâmica , Hormônios/metabolismo , Testes de Função Renal , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Poliúria/fisiopatologia , Sódio/metabolismo , Transcriptoma/genética
20.
Circulation ; 110(11): 1477-83, 2004 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-15353507

RESUMO

BACKGROUND: Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. METHODS AND RESULTS: Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, beta-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of beta1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented. CONCLUSIONS: In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Insuficiência da Valva Aórtica/tratamento farmacológico , Metoprolol/uso terapêutico , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/genética , Insuficiência da Valva Aórtica/fisiopatologia , Catecolaminas/análise , Tamanho Celular/efeitos dos fármacos , Doença Crônica , Avaliação Pré-Clínica de Medicamentos , Fibronectinas/análise , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Metoprolol/farmacologia , Miócitos Cardíacos/química , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/ultraestrutura , Tamanho do Órgão , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 1/biossíntese , Receptores Adrenérgicos beta 1/genética , Volume Sistólico , Ultrassonografia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
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