RESUMEN
AIMS: To compare the therapeutic potential of TP-113, a unique molecular entity linking DHA with metformin, for alleviating insulin resistance in obese diabetic mice through the PDX/IL-6 pathway. MATERIAL AND METHODS: We utilized the generically obese diabetic db/db mouse model for all experiments. Initial studies investigated both a dose and time course response. These results were then utilized to design a long-term (5 week) treatment protocol. Mice were gavaged twice daily with 1 of 3 treatments: 200 mg/kg BW TP113, an equivalent dose of metformin alone (70 mg/kg BW) or water. Whole-body insulin sensitivity was measured using the hyperinsulinaemic-isoglycaemic clamp procedure in awake unrestrained mice. RESULTS: We first confirmed that acute TP-113 treatment raises PDX and IL-6 levels in skeletal muscle. We next tested the long-term glucoregulatory effect of oral TP-113 in obese diabetic db/db mice and compared its effect to an equivalent dose of metformin. A 5-week oral treatment with TP-113 reduced insulin resistance compared to both vehicle treatment and metformin alone, revealed by the determination of whole-body insulin sensitivity for glucose disposal using the clamp technique. This insulin-sensitizing effect was explained primarily by improvement of insulin action to suppress hepatic glucose production in TP-113-treated mice. These effects of TP-113 were greater than that of an equivalent dose of metformin, indicating that TP-113 increases metformin efficacy for reducing insulin resistance. CONCLUSION: We conclude that TP-113 improves insulin sensitivity in obese diabetic mice through activation of the PDX/IL-6 signaling axis in skeletal muscle and improved glucoregulatory action in the liver.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácidos Docosahexaenoicos/farmacología , Glutamatos/farmacología , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Interleucina-6/metabolismo , Hígado/efectos de los fármacos , Metformina/farmacología , Músculo Esquelético/efectos de los fármacos , Obesidad/metabolismo , Animales , Glucemia/metabolismo , Modelos Animales de Enfermedad , Combinación de Medicamentos , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Hígado/metabolismo , Ratones , Ratones Obesos , Músculo Esquelético/metabolismoRESUMEN
While heart rate reduction (HRR) is a target for the management of patients with heart disease, contradictory results were reported using ivabradine, which selectively inhibits the pacemaker If current, vs. ß-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB+/+;LDLR-/-). Following a longitudinal study design, we used 3- and 6-mo-old mice, untreated or treated for 3 mo with ivabradine or metoprolol. Cardiac function was evaluated in vivo and ex vivo in working hearts perfused with 13C-labeled substrates to assess substrate fluxes through energy metabolic pathways. Compared with 3-mo-old, 6-mo-old dyslipidemic mice had similar cardiac hemodynamics in vivo but impaired (P < 0.001) contractile function (aortic flow: -45%; cardiac output: -34%; stroke volume: -35%) and glycolysis (-24%) ex vivo. Despite inducing a similar 10% HRR, ivabradine-treated hearts displayed significantly higher stroke volume values and glycolysis vs. their metoprolol-treated counterparts ex vivo, values for the ivabradine group being often not significantly different from 3-mo-old mice. Further analyses highlighted additional significant cardiac alterations with disease progression, namely in the total tissue level of proteins modified by O-linked N-acetylglucosamine (O-GlcNAc), whose formation is governed by glucose metabolism via the hexosamine biosynthetic pathway, which showed a similar pattern with ivabradine vs. metoprolol treatment. Collectively, our results emphasize the implication of alterations in cardiac glucose metabolism and signaling linked to disease progression in our mouse model. Despite similar HRR, ivabradine, but not metoprolol, preserved cardiac function and glucose metabolism during disease progression.
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Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Benzazepinas/farmacología , Fármacos Cardiovasculares/farmacología , Dislipidemias/metabolismo , Glucólisis/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Corazón/efectos de los fármacos , Metoprolol/farmacología , Animales , Bradicardia , Modelos Animales de Enfermedad , Ecocardiografía , Metabolismo Energético/efectos de los fármacos , Femenino , Glucosa/metabolismo , Hemodinámica/efectos de los fármacos , Ivabradina , Estudios Longitudinales , Masculino , Ratones , Miocardio/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Volumen Sistólico , Telemetría , TranscriptomaRESUMEN
AIMS: Calcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve. METHODS AND RESULTS: By using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed. P2Y2R-mediated mineral resorption was corroborated by using mouse VICs isolated from wild type and P2Y2R(-/-) mice. Measurements of extracellular pH (pHe) by using core-shell nanosensors revealed that P2Y2R-mediated CAXII export to the cell membrane led to an acidification of extracellular space, whereby minerals are resorbed. In vivo, we next treated LDLR(-/-)/ApoB(100/100)/IGF2 mice, which had developed CAVS under a high-fat/high-sucrose diet for 8 months, with 2-thioUTP (a P2Y2R agonist) or saline for the next 2 months. The administration of 2-thioUTP (2mg/kg/day i.p.) reduced the mineral volume in the aortic valve measured with serial microCT analyses, which improved hemodynamics and reduced left ventricular hypertrophy (LVH). Examination of leaflets at necropsy confirmed a lower level of mineralization and fibrosis along with higher levels of CAXII in mice under 2-thioUTP. In another series of experiment, the administration of acetazolamide (a CA inhibitor) prevented the acidification of leaflets and the regression of CAVS induced by 2-thioUTP in LDLR(-/-)/ApoB(100/100)/IGF2 mice. CONCLUSION: P2Y2R-mediated expression of CAXII by VICs acidifies the extracellular space and promotes the regression of CAVS.
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Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/metabolismo , Calcinosis/complicaciones , Calcinosis/metabolismo , Anhidrasas Carbónicas/metabolismo , Válvulas Cardíacas/metabolismo , Animales , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Calcinosis/patología , Modelos Animales de Enfermedad , Espacio Extracelular/metabolismo , Válvulas Cardíacas/patología , Masculino , Ratones , Ratones Transgénicos , Minerales/metabolismo , Agonistas del Receptor Purinérgico P2Y/farmacología , Receptores Purinérgicos P2Y2/metabolismoRESUMEN
OBJECTIVE: This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricular dysfunction and the development of calcified aortic valve disease using a dyslipidemic mouse model prone to developing type 2 diabetes mellitus. APPROACH AND RESULTS: When compared with nondiabetic LDLr(-/-)/ApoB(100/100), diabetic LDLr(-/-)/ApoB(100/100)/IGF-II mice exhibited similar dyslipidemia and obesity but developed type 2 diabetes mellitus when fed a high-fat/sucrose/cholesterol diet for 6 months. LDLr(-/-)/ApoB(100/100)/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr(-/-)/ApoB(100/100) mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr(-/-)/ApoB(100/100)/IGF-II mice when compared with LDLr(-/-)/ApoB(100/100). Importantly, we found that peak aortic jet velocity was significantly increased in LDLr(-/-)/ApoB(100/100)/IGF-II mice versus LDLr(-/-)/ApoB(100/100) animals on the high-fat/sucrose/cholesterol diet. Microtomography scans and Alizarin red staining indicated calcification in the aortic valves, whereas electron microscopy and energy dispersive x-ray spectroscopy further revealed mineralization of the aortic leaflets and the presence of inflammatory infiltrates in diabetic mice. Studies showed upregulation of hypertrophic genes (anp, bnp, b-mhc) in myocardial tissues and of osteogenic genes (spp1, bglap, runx2) in aortic tissues of diabetic mice. CONCLUSIONS: We have established the diabetes mellitus -prone LDLr(-/-)/ApoB(100/100)/IGF-II mouse as a new model of calcified aortic valve disease. Our results are consistent with the growing body of clinical evidence that the dysmetabolic state of type 2 diabetes mellitus contributes to early mineralization of the aortic valve and calcified aortic valve disease pathogenesis.
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Estenosis de la Válvula Aórtica/etiología , Válvula Aórtica/patología , Calcinosis/etiología , Diabetes Mellitus Tipo 2/complicaciones , Dislipidemias/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Animales , Válvula Aórtica/metabolismo , Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/fisiopatología , Apolipoproteína B-100 , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Calcinosis/diagnóstico , Calcinosis/genética , Calcinosis/metabolismo , Calcinosis/fisiopatología , Colesterol en la Dieta , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Sacarosa en la Dieta , Modelos Animales de Enfermedad , Dislipidemias/genética , Dislipidemias/metabolismo , Regulación de la Expresión Génica , Genotipo , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de Tiempo , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
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.
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Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Insuficiencia de la Válvula Aórtica/metabolismo , Metabolismo Energético/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Condicionamiento Físico Animal , Resistencia Física , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Modelos Animales de Enfermedad , Regulación hacia Abajo , Glucosa/metabolismo , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Masculino , Miocardio/metabolismo , Ratas Wistar , UltrasonografíaRESUMEN
BACKGROUND AND AIM OF THE STUDY: Aortic regurgitation (AR) is a disease for which there is currently no effective medical treatment. It has been shown previously in an experimental model of AR that the renin-angiotensin-aldosterone system (RAAS) plays a major role, and that medications blocking the RAAS are effective to protect against left ventricular (LV) hypertrophy and also help to maintain a normal systolic function. The role of aldosterone receptor blockers in this disease has never been evaluated. Thus, the effects were studied of the aldosterone receptor blocking agent spironolactone in a model of chronic AR in rats. METHODS: The effects of a six-month treatment with spironolactone were evaluated in adult Wistar rats with severe AR, compared to sham-operated and untreated AR animals. RESULTS: Spironolactone treatment decreased the total heart weight. In addition, the LV expression of atrial natriuretic peptide mRNA was decreased by spironolactone treatment, as was the expression of collagen 1 and LOX1 mRNAs. Left ventricular fibrosis was decreased by spironolactone treatment. CONCLUSION: Spironolactone protected against volume-overload cardiomyopathy in this model of aortic valve regurgitation. The predominant protective effect was a decrease in myocardial fibrosis.
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Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Cardiomegalia/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Espironolactona/farmacología , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/fisiopatología , Presión Sanguínea/efectos de los fármacos , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/fisiopatología , Enfermedad Crónica , Diástole/fisiología , Modelos Animales de Enfermedad , Ecocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Presión Ventricular/fisiologíaRESUMEN
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.
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Carbohidratos de la Dieta/efectos adversos , Fructosa/administración & dosificación , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos , Análisis de Varianza , Animales , Insuficiencia de la Válvula Aórtica/metabolismo , Insuficiencia de la Válvula Aórtica/fisiopatología , Western Blotting , Carbohidratos de la Dieta/metabolismo , Fructosa/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Masculino , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Volumen Sistólico , Triglicéridos/sangreRESUMEN
We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.
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Hipoglucemiantes/farmacología , Miofibrillas/metabolismo , Proteínas Quinasas/metabolismo , Tiazolidinedionas/farmacología , Animales , Factor Natriurético Atrial/genética , Western Blotting , Peso Corporal/efectos de los fármacos , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ecocardiografía , Glucosiltransferasas/genética , Glucógeno/metabolismo , Glucógeno Fosforilasa/genética , Glucógeno Sintasa/genética , Glicoproteínas/genética , Hemodinámica/efectos de los fármacos , Lipoproteína Lipasa/genética , Masculino , Péptido Natriurético Encefálico/genética , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratas , Ratas Sprague-Dawley , Rosiglitazona , Serina-Treonina Quinasas TOR , UTP-Glucosa-1-Fosfato Uridililtransferasa/genéticaRESUMEN
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.
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Insuficiencia de la Válvula Aórtica/complicaciones , Insuficiencia de la Válvula Aórtica/fisiopatología , Modelos Animales de Enfermedad , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Remodelación Ventricular , Enfermedad Aguda , Animales , Insuficiencia de la Válvula Aórtica/metabolismo , Presión Sanguínea/fisiología , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Frecuencia Cardíaca/fisiología , Hipertrofia Ventricular Izquierda/metabolismo , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Wistar , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/fisiología , Factor de Transcripción STAT3/metabolismoRESUMEN
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.
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Insuficiencia de la Válvula Aórtica/complicaciones , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Animales , Insuficiencia de la Válvula Aórtica/patología , Insuficiencia de la Válvula Aórtica/fisiopatología , Captopril/uso terapéutico , Fibrosis Endomiocárdica/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Hipertensión/patología , Hipertensión/fisiopatología , Hipertrofia/fisiopatología , Masculino , Tamaño de los Órganos , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Endogámicas WKYRESUMEN
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.
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Insuficiencia de la Válvula Aórtica/fisiopatología , Remodelación Ventricular , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Colágeno/genética , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Fibronectinas/genética , Masculino , Tamaño de los Órganos , Ovariectomía , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres SexualesRESUMEN
Heart disease remains a major complication of diabetes, and the identification of new therapeutic targets is essential. This study investigates the role of the protein kinase MK2, a p38 mitogen-activated protein kinase downstream target, in the development of diabetes-induced cardiomyopathy. Diabetes was induced in control (MK2(+/+)) and MK2-null (MK2(-/-)) mice using repeated injections of a low dose of streptozotocin (STZ). This protocol generated in MK2(+/+) mice a model of diabetes characterized by a 50% decrease in plasma insulin, hyperglycemia, and insulin resistance (IR), as well as major contractile dysfunction, which was associated with alterations in proteins involved in calcium handling. While MK2(-/-)-STZ mice remained hyperglycemic, they showed improved IR and none of the cardiac functional or molecular alterations. Further analyses highlighted marked lipid perturbations in MK2(+/+)-STZ mice, which encompass increased 1) circulating levels of free fatty acid, ketone bodies, and long-chain acylcarnitines and 2) cardiac triglyceride accumulation and ex vivo palmitate ß-oxidation. MK2(-/-)-STZ mice were also protected against all these diabetes-induced lipid alterations. Our results demonstrate the benefits of MK2 deletion on diabetes-induced cardiac molecular and lipid metabolic changes, as well as contractile dysfunction. As a result, MK2 represents a new potential therapeutic target to prevent diabetes-induced cardiac dysfunction.
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Diabetes Mellitus Experimental/genética , Cardiomiopatías Diabéticas/genética , Eliminación de Gen , Péptidos y Proteínas de Señalización Intracelular/genética , Metabolismo de los Lípidos/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Carnitina/análogos & derivados , Carnitina/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Hiperglucemia/genética , Insulina/sangre , Resistencia a la Insulina/genética , Cuerpos Cetónicos/metabolismo , Ratones , Contracción Muscular/genética , Estreptozocina , Triglicéridos/metabolismoRESUMEN
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.
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Antagonistas Adrenérgicos beta/uso terapéutico , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Metoprolol/uso terapéutico , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/genética , Insuficiencia de la Válvula Aórtica/fisiopatología , Catecolaminas/análisis , Tamaño de la Célula/efectos de los fármacos , Enfermedad Crónica , Evaluación Preclínica de Medicamentos , Fibronectinas/análisis , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/prevención & control , Masculino , Metoprolol/farmacología , Miocitos Cardíacos/química , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/ultraestructura , Tamaño de los Órganos , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptores Adrenérgicos beta 1/biosíntesis , Receptores Adrenérgicos beta 1/genética , Volumen Sistólico , Ultrasonografía , Regulación hacia Arriba/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Dobutamine stress echocardiography is used to investigate a wide variety of heart diseases in humans. Dobutamine stress echocardiography has also been used in animal models of heart disease despite the facts that the normal response of healthy rat hearts to this type of pharmacological stress testing is unknown. This study was performed to assess this normal response. METHODS: 15 normal adult male Wistar rats were evaluated. Increasing doses of dobutamine were infused intravenously under continuous imaging of the heart by a 12 MHz ultrasound probe. RESULTS: Dobutamine stress echocardiography reduced gradually LV diastolic and systolic dimensions. Ejection fraction increased by a mean of +24% vs. baseline. Heart rate increased progressively without reaching a plateau. Changes in LV dimensions and ejection fraction reached a plateau after a mean of 4 minutes at a constant infusion rate. CONCLUSION: DSE can be easily performed in rats. The normal response is an increase in heart rate and ejection fraction and a decrease in LV dimensions. A plateau in echocardiographic measurements is obtained after 4 minutes of a constant infusion rate in most animals.
Asunto(s)
Dobutamina/administración & dosificación , Ecocardiografía/métodos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/diagnóstico por imagen , Función Ventricular Izquierda/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Prueba de Esfuerzo , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Masculino , Ratas , Ratas Wistar , Volumen Sistólico/efectos de los fármacosRESUMEN
Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA ß-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling.
Asunto(s)
Insuficiencia de la Válvula Aórtica/genética , Metabolismo Energético/genética , Insuficiencia Cardíaca/genética , Hipertrofia Ventricular Izquierda/genética , Animales , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Insuficiencia de la Válvula Aórtica/fisiopatología , Volumen Cardíaco/genética , Modelos Animales de Enfermedad , Fenofibrato/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Mitocondrias Cardíacas/genética , Oxidación-Reducción , PPAR alfa/genética , Ratas , Transcriptoma , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/genéticaRESUMEN
BACKGROUND: Aortic regurgitation (AR) is a chronic disease for which there is currently no approved medical treatment. We previously reported in an animal model that ß-blockade with metoprolol exerted beneficial effects on left ventricular remodeling and survival. Despite the recent publication of promising human data, ß-blockade in chronic AR remains controversial. More data are needed to support this potentially new treatment strategy. We hypothesized that carvedilol might be another safe treatment option in chronic AR, considering its combined ß-blocking and α-blocking effects and proven efficacy in patients with established heart failure. METHODS AND RESULTS: The effects of a 6-month treatment with carvedilol 30 mg/kg/d orally were evaluated in adult Wistar rats with severe AR. Sham-operated and untreated AR animals were used as controls. Carvedilol treatment resulted in less left ventricular hypertrophy and dilatation. Ejection fraction was improved and filling pressures were reduced by carvedilol. ß1-Receptor expression was also improved as well as myocardial capillary density. Those beneficial effects were noted despite the presence of drug-induced bradycardia. CONCLUSIONS: Carvedilol exerted protective effects against volume-overload cardiomyopathy in this model of aortic valve regurgitation with preserved ejection fraction. These results suggest a protective class effect of ß-blockers. Combined with the recent publication of promising human data, our findings support the need to carefully design a prospective study in humans to evaluate the effects of ß-blockers in chronic aortic valve regurgitation.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Carbazoles/farmacología , Propanolaminas/farmacología , Administración Oral , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/efectos adversos , Animales , Insuficiencia de la Válvula Aórtica/complicaciones , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/genética , Insuficiencia de la Válvula Aórtica/fisiopatología , Factor Natriurético Atrial/genética , Bradicardia/inducido químicamente , Capilares/efectos de los fármacos , Capilares/fisiopatología , Carbazoles/administración & dosificación , Carbazoles/efectos adversos , Carvedilol , Enfermedad Crónica , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/genética , Proteínas Relacionadas con la Folistatina/genética , Regulación de la Expresión Génica , Frecuencia Cardíaca/efectos de los fármacos , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/prevención & control , Masculino , Péptido Natriurético Encefálico/genética , Propanolaminas/administración & dosificación , Propanolaminas/efectos adversos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Adrenérgicos/genética , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Ultrasonografía , Función Ventricular Izquierda/efectos de los fármacos , Presión Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Aortic regurgitation (AR) is a disease of chronic left ventricular (LV) volume overload. Over time, AR will lead to LV dilatation, hypertrophy, and loss of function. There is currently no medical treatment proven effective to slow the evolution of this cardiomyopathy. Vasodilators were once thought to have protective effects, but recent publications have cast some doubts about their effectiveness. We hypothesized that drugs targeting the renin-angiotensin system should be more effective than those having no direct effect on the renin-angiotensin system. METHODS AND RESULTS: We designed a protocol comparing the effects of 3 vasodilators in a rat AR model (n=9 to 11 animals per group). The effects of a 6-month treatment of (1) nifedipine, (2) captopril, or (3) losartan were compared in male AR rats. Sham-operated and untreated AR animals were used as controls. Nifedipine-treated animals displayed hemodynamics, LV dilatation, hypertrophy, and loss of function similar to those of the untreated group. Both captopril and losartan were effective in improving hemodynamics, slow LV dilatation, hypertrophy, and dysfunction. Gene expression analysis confirmed the lack of effects of the nifedipine treatment at the molecular level. CONCLUSIONS: Using an animal model of severe AR, we found that vasodilators targeting the renin-angiotensin system were effective to slow the development of LV remodeling and to preserve LV function. As recently shown in the most recent human clinical trial, nifedipine was totally ineffective. Targeting the renin-angiotensin system seems a promising avenue in the treatment of this disease, and clinical trials should be carefully designed to re-evaluate the effectiveness of angiotensin I-converting enzyme inhibitors or angiotensin II receptor blockers in AR.
Asunto(s)
Insuficiencia de la Válvula Aórtica/complicaciones , Cardiomiopatía Dilatada/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Vasodilatadores/uso terapéutico , Función Ventricular Izquierda/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Captopril/administración & dosificación , Captopril/uso terapéutico , Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/fisiopatología , Enfermedad Crónica , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ecocardiografía Doppler , Estudios de Seguimiento , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Losartán/administración & dosificación , Losartán/uso terapéutico , Masculino , Nifedipino/administración & dosificación , Nifedipino/uso terapéutico , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Resultado del Tratamiento , Vasodilatadores/administración & dosificación , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
BACKGROUND: Exercise training has beneficial effects in patients with heart failure, although there is still no clear evidence that it may impact on their survival. There are no data regarding the effects of exercise in subjects with chronic left ventricular (LV) volume overload. Using a rat model of severe aortic valve regurgitation (AR), we studied the effects of long-term exercise training on survival, development of heart failure, and LV myocardial remodeling. METHODS AND RESULTS: One hundred sixty male adult rats were divided in 3 groups: sham sedentary (n=40), AR sedentary (n=80), and AR trained (n=40). Training consisted in treadmill running for up to 30 minutes, 5 times per week for 9 months, at a maximal speed of 20 m/minute. All sham-operated animals survived the entire course of the protocol. After 9 months, 65% of trained animals were alive compared with 46% of sedentary ones (P=0.05). Ejection fractions remained in the normal range (all above 60%) and LV masses between AR groups were similar. There was significantly less LV fibrosis in the trained group and lower LV filling pressures and improved echocardiographic diastolic parameters. Heart rate variability was also improved by exercise. CONCLUSIONS: Our data show that moderate endurance training is safe, does not increase the rate of developing heart failure, and most importantly, improves survival in this animal model of chronic LV volume overload. Exercise improved LV diastolic function, heart rate variability, and reduced myocardial fibrosis.
Asunto(s)
Insuficiencia de la Válvula Aórtica/complicaciones , Terapia por Ejercicio , Insuficiencia Cardíaca/terapia , Disfunción Ventricular Izquierda/terapia , Remodelación Ventricular , Animales , Insuficiencia de la Válvula Aórtica/fisiopatología , Presión Sanguínea , Modelos Animales de Enfermedad , Fibrosis , Regulación de la Expresión Génica , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca , Masculino , Miocardio/metabolismo , Miocardio/patología , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Índice de Severidad de la Enfermedad , Factores de Tiempo , Ultrasonografía , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatología , Presión VentricularRESUMEN
Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV), which results in dilation, eccentric hypertrophy, and eventually loss of function. Little is known about the impact of AR on LV gene expression. We, therefore, conducted a gene expression profiling study in the LV of rats with acute and severe AR. We identified 64 genes that were specifically upregulated and 29 that were downregulated out of 21,910 genes after 2 wk. Of the upregulated genes, a good proportion was related to the extracellular matrix. We subsequently studied a subset of 19 genes by quantitative RT-PCR (qRT-PCR) to see if the modulation seen in the LV after 2 wk persisted in the chronic phase (after 6 and 12 mo) and found that it did persist. Knowing that the adrenergic and renin-angiotensin systems are overactivated in our animal model, we were interested to see if blocking those systems using metoprolol (25 mg.kg(-1).day(-1)) and captopril (100 mg.kg(-1).day(-1)) would alter the expression of some upregulated LV genes in AR rats after 6 mo. By qRT-PCR, we observed that upregulations of LV mRNA levels encoding for procollagens type I and III, fibronectin, atrial natriuretic peptide, transforming growth factor-beta(2), and connective tissue growth factor were totally or partially reversed by this treatment. These observations provide a molecular rationale for a medical strategy aiming these systems in the medical treatment of AR and expand the paradigm in the study of this form of LV volume overload.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Perfilación de la Expresión Génica , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Receptores Adrenérgicos beta/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Enfermedad Aguda , Animales , Insuficiencia de la Válvula Aórtica/complicaciones , Insuficiencia de la Válvula Aórtica/genética , Insuficiencia de la Válvula Aórtica/metabolismo , Captopril/farmacología , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/metabolismo , Masculino , Metoprolol/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Adrenérgicos beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
BACKGROUND: Aortic valve regurgitation (AR) imposes a pathologic volume overload to the left ventricle (LV), whereas aerobic exercise causes physiologic volume overloading. The impact of combining both LV volume overloads (pathologic and physiologic) is unknown. Considering the known beneficial effects of aerobic training on the cardiovascular system, we hypothesized that the positive effects would outweigh the negative ones and that exercise would improve the tolerance of the LV to AR. METHODS: Forty female adult Wistar rats were randomly divided in the following groups: 1) sham sedentary (SS), 2) sham trained (ST), 3) AR sedentary (ARS), and 4) AR trained (ART). Training consisted in treadmill running for 30 min five times per week at 20 m x s(-1) for 24 wk. In vivo follow-up was made by echocardiography and invasive intracardiac pressure measurements. Hearts were harvested for tissue analysis. RESULTS: Echocardiography revealed less LV dilation and hypertrophy in ART versus ARS as well as improved myocardial performance index. LV ejection fractions remained similar and within normal range in ART versus ARS. Invasive cardiac pressures yielded improved dP/dt- in ART versus ARS but similar dP/dt+. beta(1)-Adrenergic receptor mRNA expression was improved in the ART group versus ARS. CONCLUSION: Our data suggest that a moderate aerobic exercise program helps minimize LV dilation and hypertrophy and improves diastolic cardiac performance in heart submitted to chronic volume overload due to severe aortic valve regurgitation in this animal model.