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OBJECTIVE: Qiliqiangxin Capsule (QL) was investigated for its possible role in cardiac hypertrophy in this study. METHODS: QL (0.5 mg/mL) was pre-treated in Neonatal Mouse Ventricular Cardiomyocytes (NMVCs) before induction of cardiomyocyte hypertrophy by Angiotensin II (Ang-II). Immunofluorescence staining for α-actinin was conducted to determine cell surface area. Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) of hypertrophy markers were examined. Ang-II infusion was given to stimulate cardiac hypertrophy in mice. The cardiac function of mice was detected by echocardiography, and the pathological status of myocardial tissue was observed. RESULTS: The surface of cardiomyocytes was enlarged by Ang-II, and ANP and BNP levels were increased. QL processing could save these changes. miR-382-5p was upregulated in Ang-II-treated NMVCs, and reducing miR-382-5p could further enhance the therapeutic effect of QL while elevating miR-382-5p weakened the protective effect of QL. QL could inhibit miR-382-5p expression to negatively regulate Activated Transcription Factor 3 (ATF3) expression. Enhancing ATF3 expression rescued miR-382-5p upregulation-mediated role in NMVCs. In addition, QL alleviated Ang-II-stimulated cardiac hypertrophy and cardiac dysfunction in mice. CONCLUSION: QL may alleviate cardiac hypertrophy and cardiac dysfunction via the miR-382-5p/ATF3 axis.
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Factor de Transcripción Activador 3 , Angiotensina II , Cardiomegalia , Medicamentos Herbarios Chinos , MicroARNs , Miocitos Cardíacos , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , MicroARNs/metabolismo , Cardiomegalia/tratamiento farmacológico , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Factor de Transcripción Activador 3/metabolismo , Angiotensina II/farmacología , Factor Natriurético Atrial , Masculino , Péptido Natriurético Encefálico/metabolismo , Ratones , Ratones Endogámicos C57BL , Ecocardiografía , Regulación hacia Arriba/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
ABSTRACT: Angiotensin (Ang)-(1-7) is a cardioprotective peptide of the renin-angiotensin system. Prepuberty has been considered as a later susceptible window of development, and stressful factors in this life phase can induce chronic diseases in adulthood. We aimed to investigate whether the treatment with Ang-(1-7) during the prepuberty could attenuate the development of hypertension and cardiac injury in adult spontaneously hypertensive rats (SHRs). SHRs were treated with Ang-(1-7) (24 µg/kg/h) from age 4 to 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography up to 17th week. Thereafter, echocardiography was performed, and the rats were euthanized for the collection of tissues and blood. Ang-(1-7) did not change the systolic blood pressure but reduced the septal and posterior wall thickness, and cardiomyocyte hypertrophy and fibrosis in SHR. In addition, Ang-(1-7) reduced the gene expression of atrial natriuretic peptide and brain natriuretic peptide, increased the metalloproteinase 9 expression, and reduced the extracellular signal-regulated kinases 1/2 phosphorylation. Ang-(1-7) also prevented the reduction of Mas receptor but did not change the protein expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, AT1, and AT2. The treatment with Ang-(1-7) decreased the malondialdehyde (MDA) levels and increased superoxide dismutase-1 and catalase activities and protein expression of catalase. Our findings demonstrate that the treatment of SHR with Ang-(1-7) for 3 weeks early in life promotes beneficial effects in the heart later in life, even without altering blood pressure, through mechanisms involving the reduction of oxidative stress and ERK1/2 phosphorylation. In addition, this study supports the prepuberty as an important programming window.
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Angiotensina I , Presión Sanguínea , Cardiomegalia , Hipertensión , Estrés Oxidativo , Fragmentos de Péptidos , Ratas Endogámicas SHR , Animales , Angiotensina I/farmacología , Fragmentos de Péptidos/farmacología , Masculino , Hipertensión/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/prevención & control , Cardiomegalia/prevención & control , Cardiomegalia/fisiopatología , Cardiomegalia/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Estrés Oxidativo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Ratas , Fosforilación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Factores de Edad , Metaloproteinasa 9 de la Matriz/metabolismo , Factor Natriurético Atrial/metabolismo , Antihipertensivos/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Oxidative stress and MMP activity are found in the hearts and arteries in hypertension and contribute to the resulting hypertrophy and dysfunction. Quercetin is a flavonoid that reduces MMP-2 activity and ameliorates hypertrophic vascular remodeling of hypertension. The hypothesis is that treatment of hypertensive rats with quercetin ameliorates coronary maladaptive remodeling and decreases hypertrophic cardiac dysfunction by decreasing oxidative stress and MMP activity. Male Sprague-Dawley two-kidney, one-clip (2K1C) and Sham rats were treated with quercetin (10 mg/kg/day) or its vehicle for 8 weeks by gavage. Rats were analyzed at 10 weeks of hypertension. Systolic blood pressure (SBP) was examined by tail-cuff plethysmography. Cardiac left ventricles were used to determine MMP activity by in situ zymography and oxidative stress by dihydroethidium. Immunofluorescence was performed to detect transforming growth factor (TGF)-ß and nuclear factor kappa B (NFkB). Morphological analyses of heart and coronary arteries were done by H&E and picrosirius red, and cardiac function was measured by Langendorff. SBP was increased in 2K1C rats, and quercetin did not reduce it. However, quercetin decreased both oxidative stress and TGF-ß in the left ventricles of 2K1C rats. Quercetin also decreased the accentuated MMP activity in left ventricles and coronary arteries of 2K1C rats. Quercetin ameliorated hypertension-induced coronary arterial hypertrophic remodeling, although it did not reduce cardiac hypertrophic remodeling and dysfunction. Quercetin decreases cardiac oxidative stress and TGF-ß and MMP activity in addition to improving coronary remodeling, yet does not ameliorate cardiac dysfunction in 2K1C rats.
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Hipertensión Renovascular , Hipertensión , Enfermedades Renales , Ratas , Masculino , Animales , Quercetina/farmacología , Quercetina/uso terapéutico , Hipertensión Renovascular/metabolismo , Vasos Coronarios/metabolismo , Ratas Wistar , Ratas Sprague-Dawley , Hipertensión/tratamiento farmacológico , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Presión Sanguínea , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
It has been demonstrated that supplementation with the two main omega 3 polyunsaturated fatty acids (ω3 FAs), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), leads to modifications in the cardiac physiology. ω3 FAs can affect the membrane's lipid composition, as well as proteins' location and/or function. The Na+/H+ exchanger (NHE1) is an integral membrane protein involved in the maintenance of intracellular pH and its hyperactivity has been associated with the development of various cardiovascular diseases such as cardiac hypertrophy. Our aim was to determine the effect of ω3 FAs on systolic blood pressure (SBP), lipid profiles, NHE1 activity, and cardiac function in spontaneously hypertensive rats (SHR) using Wistar rats (W) as normotensive control. After weaning, the rats received orally ω3 FAs (200 mg/kg body mass/day/ 4 months). We measured SBP, lipid profiles, and different echocardiography parameters, which were used to calculate cardiac hypertrophy index, systolic function, and ventricular geometry. The rats were sacrificed, and ventricular cardiomyocytes were obtained to measure NHE1 activity. While the treatment with ω3 FAs did not affect the SBP, lipid analysis of plasma revealed a significant decrease in omega-6/omega-3 ratio, correlated with a significant reduction in left ventricular mass index in SHR. The NHE1 activity was significantly higher in SHR compared with W. While in W the NHE1 activity was similar in both groups, a significant decrease in NHE1 activity was detected in SHRs supplemented with ω3 FAs, reaching values comparable with W. Altogether, these findings revealed that diet supplementation with ω3 FAs since early age prevents the development of cardiac hypertrophy in SHR, perhaps by decreasing NHE1 activity, without altering hemodynamic overload.
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Ácidos Grasos Omega-3 , Ratas , Animales , Ratas Wistar , Ácidos Grasos Omega-3/farmacología , Ácidos Docosahexaenoicos , Ácido Eicosapentaenoico , Ratas Endogámicas SHR , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/prevención & controlRESUMEN
Aims. The cardiobenefits of empagliflozin are multidimensional, and some mechanisms are still unclear. The aim of the present study was to evaluate the effect of treatment with empagliflozin on biometric parameters and gene expression in the local cardiac RAS, oxidative stress, and endoplasmic reticulum pathways in a mouse model. Main Methods. Forty male C57BL/6 mice were fed with control (C) or high-fat (HF) diets for 10 weeks. After that, the groups were redistributed according to the treatment with empagliflozin-CE or HFE. The empagliflozin was administered via food for 5 weeks (10 mg/kg/day). We performed biochemical analyses, blood pressure monitoring, oral glucose tolerance test, left ventricle (LV) stereology, RT-qPCR for genes related to classical and counterregulatory local RAS, oxidative stress, and endoplasmic reticulum stress. Key Findings. In comparison to HF, HFE decreased body mass and improved glucose intolerance and insulin resistance. The cardiac parameters were enhanced after treatment as expressed by decrease in plasma cholesterol, plasma uric acid, and systolic blood pressure. In addition, LV analysis showed that empagliflozin reduces cardiomyocyte area and LV thickness. The local RAS had less activity of the classical pathway and positive effects on the counterregulatory pathway. Empagliflozin treatment also decreased oxidative stress and endoplasmic reticulum stress-related genes. Significance. Our results suggests that empagliflozin modulates the local RAS pathway towards alleviation of oxidative stress and ER stress in the LV, which may be a route to its effects on improved cardiac remodeling.
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Compuestos de Bencidrilo/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Glucósidos/uso terapéutico , Ventrículos Cardíacos , Angiotensinas , Animales , Hipertrofia , Masculino , Ratones , Ratones Endogámicos C57BL , ReninaRESUMEN
Typically, healthy cardiac tissue utilizes more fat than any other organ. Cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids to support the high energetic demand. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. Given the beneficial effects of calorie restriction, we hypothesized that calorie restriction prevents cardiac hypertrophy, lipid content changes, mitochondrial and redox dysregulation. Strikingly, calorie restriction reversed isoproterenol-induced cardiac hypertrophy. Isolated mitochondria from hypertrophic hearts produced significantly higher levels of succinate-driven H2O2 production, which was blocked by calorie restriction. Cardiac hypertrophy lowered mitochondrial respiratory control ratios, and decreased superoxide dismutase and glutathione peroxidase levels. These effects were also prevented by calorie restriction. We performed lipidomic profiling to gain insights into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy. Calorie restriction protected against the consumption of several triglycerides (TGs) linked to unsaturated fatty acids. Also, this dietary procedure protected against the accumulation of TGs containing saturated fatty acids observed in hypertrophic samples. Cardiac hypertrophy induced an increase in ceramides, phosphoethanolamines, and acylcarnitines (12:0, 14:0, 16:0, and 18:0). These were all reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances, and oxidative stress. These changes are prevented (at least partially) by calorie restriction intervention in vivo. This study uncovers the potential for calorie restriction to become a new therapeutic intervention against cardiac hypertrophy, and mechanisms in which it acts.
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Restricción Calórica , Lipidómica , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/prevención & control , Humanos , Peróxido de Hidrógeno/metabolismo , Isoproterenol/metabolismo , Isoproterenol/toxicidad , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés OxidativoRESUMEN
OBJECTIVES: To determine the efficacy and adverse events of the administration of angiotensin--converting enzyme inhibitors for the management of preclinical myxomatous mitral valve disease in dogs. MATERIALS AND METHODS: A compre- hensive search using Pubmed/MEDLINE, LILACS and CAB abstracts databases was performed. Ran- domised clinical trials that assessed efficacy and adverse events of angiotensin-converting enzyme inhibitors for the management of preclinical myxomatous mitral valve disease in dogs were included. Certainty of evidence was rated using GRADE methods. RESULTS: Four randomised clinical trials were included. While safe, angiotensin-converting enzyme inhibitors administration to dogs with myxomatous mitral valve disease and cardiomegaly results in little to no difference in the risk of development congestive heart failure (high certainty of evidence; relative risk: 1.03; 95% confidence interval: 0.87 to 1.23) and may result in little to no difference in cardiovascular-related (low certainty of evidence; relative risk: 1.01; 95% confidence interval: 0.54 to 1.89) and all-cause mortality (low certainty of evidence; relative risk: 0.93; 95% confidence interval: 0.63 to 1.36). Administration of angiotensin-converting enzyme inhibitors to dogs with myxomatous mitral valve disease without cardiomegaly may result in a reduced risk of congestive heart failure development. However, the range in which the actual effect for this outcome may be, the "margin of error," indicates it might also increase the risk of congestive heart failure development (low certainty of evidence; relative risk: 0.86; 95% confidence interval: 0.54 to 1.35). CLINICAL SIGNIFICANCE: Administration of angiotensin-converting enzyme inhibitors to dogs with -preclinical myxoma- tous mitral valve disease and cardiomegaly results in little to no difference in the risk of the develop- ment of congestive heart failure and may result in little to no difference in -cardiovascular-related and all-cause mortality. The certainty of evidence of the efficacy of angiotensin-converting enzyme inhibi- tors administration to dogs without cardiomegaly was low.
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Enfermedades de los Perros , Insuficiencia Cardíaca , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Angiotensinas/uso terapéutico , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Perros , Insuficiencia Cardíaca/veterinaria , Válvula MitralRESUMEN
Obesity is recognized as an independent risk factor for cardiovascular diseases and is an important contributor to cardiac mortality. Açaí seed extract (ASE), rich in proanthocyanidins, has been shown to have potential anti-obesity effects. This study aimed to investigate the therapeutic effect of ASE in cardiovascular remodeling associated with obesity and compare it with that of rosuvastatin. Male C57BL/6 mice were fed a high-fat diet or a standard diet for 12 weeks. The ASE (300 mg/kg/day) and rosuvastatin (20 mg/kg/day) treatments started in the 8th week until the 12th week, totaling 4 weeks of treatment. Our data showed that treatment with ASE and rosuvastatin reduced body weight, ameliorated lipid profile, and improved cardiovascular remodeling. Treatment with ASE but not rosuvastatin reduced hyperglycemia and oxidative stress by reducing immunostaining of 8-isoprostane and increasing SOD-1 and GPx expression in HFD mice. ASE and rosuvastatin reduced NOX4 expression, increased SIRT-1 and Nrf2 expression and catalase and GPx activities, and improved vascular and cardiac remodeling in HFD mice. The therapeutic effect of ASE was similar to that of rosuvastatin in reducing dyslipidemia and cardiovascular remodeling but was superior in reducing oxidative damage and hyperglycemia, suggesting that ASE was a promising natural product for the treatment of cardiovascular alterations associated with obesity.
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Antioxidantes/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Obesidad/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Remodelación Ventricular/efectos de los fármacos , Animales , Cardiomegalia/etiología , Dieta Alta en Grasa , Euterpe/química , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/complicaciones , Proantocianidinas/uso terapéutico , Semillas/químicaRESUMEN
BACKGROUND: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. METHODS: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague-Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. RESULTS: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-ß1 and gene expression of pro-remodeling molecules TGF-ß1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. CONCLUSIONS: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.
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Antihipertensivos/farmacología , Cardiomegalia/tratamiento farmacológico , Fibrosis/tratamiento farmacológico , Corazón/efectos de los fármacos , Hidroclorotiazida/farmacología , Hipertensión/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/metabolismo , Quinasas Asociadas a rho/metabolismoRESUMEN
AIMS: Despite the broad pharmacological arsenal to treat hypertension, chronic patients may develop irreversible cardiac remodeling and fibrosis. Angiotensin II, the main peptide responsible for the Renin-Angiotensin-Aldosterone-System, has been closely linked to cardiac remodeling, hypertrophy, fibrosis, and hypertension, and some of these effects are induced by inflammatory mediators. Resolvin-D1 (RvD1) elicits potent anti-inflammatory and pro-resolving effects in various pathological models. In this study, we aimed to examine whether RvD1 ameliorates cardiac remodeling and hypertension triggered by angiotensin II. METHODS AND RESULTS: Alzet® osmotic mini-pumps filled with angiotensin II (1.5 mg/kg/day) were implanted in male C57BL/6 J mice for 7 or 14 days. RvD1 (3 µg/kg/day, i.p) was administered one day after the surgery and during the complete infusion period. Blood pressure and myocardial functional parameters were assessed by echocardiography. At the end of the experimental procedure, blood and heart tissue were harvested, and plasma and histological parameters were studied. After 7 and 14 days, RvD1 reduced the increase of neutrophil and macrophage infiltration triggered by angiotensin II, and also reduced ICAM-1 and VCAM-1 expression levels. RvD1 also reduced cytokine plasma levels (IL-1ß, TNF-α, IL-6, KC, MCP-1), cardiac hypertrophy, interstitial and perivascular fibrosis, and hypertension. CONCLUSIONS: This study unveils novel cardioprotective effects of RvD1 in angiotensin II-induced hypertension and cardiac remodeling by attenuating inflammation and provides insights into a potential clinical application.
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Cardiomegalia/tratamiento farmacológico , Ácidos Docosahexaenoicos/farmacología , Hipertensión/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Angiotensina II/efectos adversos , Angiotensina II/farmacología , Animales , Cardiomegalia/sangre , Cardiomegalia/genética , Cardiomegalia/patología , Quimiocina CCL2/sangre , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipertensión/sangre , Hipertensión/genética , Hipertensión/patología , Inflamación/sangre , Inflamación/genética , Inflamación/patología , Molécula 1 de Adhesión Intercelular/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Ratones , Sistema Renina-Angiotensina/genética , Factor de Necrosis Tumoral alfa/sangre , Molécula 1 de Adhesión Celular Vascular/sangre , Remodelación VentricularRESUMEN
Oxidative stress, characterized by the accumulation of reactive oxygen species (ROS), is implicated in the pathogenesis of several diseases, including cardiac hypertrophy. The flavonoid quercetin is a potent ROS scavenger, with several beneficial effects for the cardiovascular system, including antihypertrophic effects. Oxidative imbalance has been implicated in cardiac hypertrophy and heart failure. In this work, we tested whether quercetin could attenuate cardiac hypertrophy by improving redox balance and mitochondrial homeostasis. To test this hypothesis, we treated a group of mice with isoproterenol (30 mg/kg/day) for 4 or 8 consecutive days. Another group received quercetin (10 mg/kg/day) from day 5th of isoproterenol treatment. We carried out the following assays in cardiac tissue: measurement of cardiac hypertrophy, protein sulfhydryl, catalase, Cu/Zn and Mn-superoxide dismutase (SOD) activity, detection of H2O2, and opening of the mitochondrial permeability transition pore. The animals treated with isoproterenol for the initial 4 days showed increased cardiac weight/tibia length ratio, decreased protein sulfhydryl content, compromised SOD and catalase activity, and high H2O2 levels. Quercetin was able to attenuate cardiac hypertrophy, restore protein sulfhydryl, and antioxidant activity, in addition to efficiently blocking the H2O2. We also observed that isoproterenol decreases mitochondrial SOD activity, while quercetin reverses it. Strikingly, quercetin also protects mitochondria against the opening of mitochondrial permeability transition pore. Taken together, these results suggest that quercetin is capable of reversing established isoproterenol-induced cardiac hypertrophy through the restoration of cellular redox balance and protecting mitochondria.
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Antioxidantes/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Quercetina/uso terapéutico , Animales , Antioxidantes/farmacología , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Catalasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Isoproterenol , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miocardio/metabolismo , Quercetina/farmacología , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Cardiac hypertrophy involves marked wall thickening or chamber enlargement. If sustained, this condition will lead to dysfunctional mitochondria and oxidative stress. Mitochondria have ATP-sensitive K+ channels (mitoKATP) in the inner membrane that modulate the redox status of the cell. OBJECTIVE: We investigated the in vivo effects of mitoKATP opening on oxidative stress in isoproterenol- induced cardiac hypertrophy. METHODS: Cardiac hypertrophy was induced in Swiss mice treated intraperitoneally with isoproterenol (ISO - 30 mg/kg/day) for 8 days. From day 4, diazoxide (DZX - 5 mg/kg/day) was used in order to open mitoKATP (a clinically relevant therapy scheme) and 5-hydroxydecanoate (5HD - 5 mg/kg/day) or glibenclamide (GLI - 3 mg/kg/day) were used as mitoKATP blockers. RESULTS: Isoproterenol-treated mice had elevated heart weight/tibia length ratios (HW/TL). Additionally, hypertrophic hearts had elevated levels of carbonylated proteins and Thiobarbituric Acid Reactive Substances (TBARS), markers of protein and lipid oxidation. In contrast, mitoKATP opening with DZX avoided ISO effects on gross hypertrophic markers (HW/TL), carbonylated proteins and TBARS, in a manner reversed by 5HD and GLI. Moreover, DZX improved mitochondrial superoxide dismutase activity. This effect was also blocked by 5HD and GLI. Additionally, ex vivo treatment of isoproterenol- induced hypertrophic cardiac tissue with DZX decreased H2O2 production in a manner sensitive to 5HD, indicating that this drug also acutely avoids oxidative stress. CONCLUSION: Our results suggest that diazoxide blocks oxidative stress and reverses cardiac hypertrophy. This pharmacological intervention could be a potential therapeutic strategy to prevent oxidative stress associated with cardiac hypertrophy.
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Cardiomegalia/tratamiento farmacológico , Diazóxido/uso terapéutico , Peróxido de Hidrógeno/metabolismo , Canales de Potasio/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/metabolismo , Diazóxido/farmacología , Evaluación Preclínica de Medicamentos , Transporte Iónico/efectos de los fármacos , Isoproterenol/toxicidad , Ratones , Estrés Oxidativo/efectos de los fármacos , Potasio/metabolismo , Carbonilación Proteica/efectos de los fármacos , Sustancias Reactivas al Ácido Tiobarbitúrico/análisisAsunto(s)
Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/uso terapéutico , Miocardio/metabolismo , Uremia/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Presión Sanguínea , Huesos/metabolismo , Cardiomegalia/complicaciones , Electrocardiografía , Factores de Crecimiento de Fibroblastos/sangre , Fibrosis , Riñón/fisiopatología , Proteínas Klotho , Masculino , Minerales/metabolismo , Miocardio/patología , Tamaño de los Órganos , Ratas Wistar , Canales Catiónicos TRPC/metabolismo , Tibia/patología , Uremia/complicaciones , Uremia/diagnóstico por imagen , Uremia/fisiopatología , Remodelación VentricularRESUMEN
AIMS: Increased activity of calpain-1 and matrix metalloproteinase (MMP)-2 was observed in different models of arterial hypertension and contribute to thicken the left ventricle (LV) walls and to hypertrophy cardiac myocytes. MMP-2 activity may be regulated by calpain-1 via bioactive molecules activation such as transforming growth factor (TGF)-ß in cardiovascular diseases. This study analyzed whether calpain-1 causes cardiac hypertrophy and dysfunction by modulating the expression and activity of MMP-2 in renovascular hypertension. MAIN METHODS: Male Wistar rats were submitted to two kidneys, one clip (2K1C) model of hypertension or sham surgery and were treated with verapamil (VRP, 8 mg/kg/bid) by gavage from the second to tenth week post-surgery. Systolic blood pressure (SBP) was weekly assessed by tail-cuff plethysmography and morphological and functional parameters of LV were analyzed by echocardiography. MMP-2 activity was analyzed by in situ and gelatin zymography, while calpain-1 activity by caseinolytic assay. MMP-2, calpain-1, TGF-ß and MMP-14/TIMP-2 levels were identified in the LV by western blots. Fluorescence assays were performed to evaluate oxidative stress, MMP-2 and calpain-1 levels. KEY FINDINGS: SBP increased in 2K1C rats and was unaltered by VRP. However, VRP notably ameliorated hypertension-induced increase in LV thickness. VRP decreased hypertension-induced enhances in calpain-1 and MMP-2 activities, oxidative stress and mature TGF-ß levels. Treatment with VRP also decreased the accentuated MMP-14/TIMP-2 levels in 2K1C. SIGNIFICANCE: Treatment with VRP decreases calpain-1 and MMP-2 activities and also reduces TGF-ß and MMP-14/TIMP-2 levels in the LV of hypertensive rats, thus contributing to ameliorate cardiac hypertrophy.
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Calpaína/metabolismo , Cardiomegalia/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/complicaciones , Metaloproteinasa 2 de la Matriz/metabolismo , Remodelación Ventricular/efectos de los fármacos , Verapamilo/farmacología , Animales , Calpaína/genética , Cardiomegalia/etiología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Ratas , Ratas Wistar , Vasodilatadores/farmacologíaRESUMEN
Abstract Background: Trimetazidine (TMZ) is an anti-ischemic drug. In spite of its protective effects on cardiovascular system, there is no scientific study on the usefulness of TMZ treatment for prolonged QT interval and cardiac hypertrophy induced by diabetes. Objectives: To evaluate the effects of TMZ on QT interval prolongation and cardiac hypertrophy in the diabetic rats. Methods: Twenty-four male Sprague-Dawley rats (200-250 g) were randomly assigned into three groups (n = 8) by simple random sampling method. Control (C), diabetic (D), and diabetic administrated with TMZ at 10 mg/kg (T10). TMZ was administrated for 8 weeks. The echocardiogram was recorded before isolating the hearts and transfer to a Langendorff apparatus. Hemodynamic parameters, QT and corrected QT interval (QTc) intervals, heart rate and antioxidant enzymes were measured. The hypertrophy index was calculated. The results were evaluated by one-way ANOVA and paired t-test using SPSS (version 16) and p < 0.05 was regarded as significant. Results: The diabetic rats significantly indicated increased hypertrophy, QT and QTc intervals and decreased Left ventricular systolic pressure (LVSP), Left ventricular developed pressure (LVDP), rate pressure product (RPP), Max dp/dt, and min dp/dt (±dp/dt max), heart rate, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase in the heart. Treatment with TMZ in the diabetic animals was significantly improved these parameters in comparison to the untreated diabetic group. Conclusions: TMZ improves QTc interval prolongation and cardiac hypertrophy in diabetes.
Resumo Fundamento: A trimetazidina (TMZ) é uma droga anti-isquêmica. Apesar de seus efeitos protetores sobre o sistema cardiovascular, não há estudos científicos sobre a utilidade do tratamento com TMZ para o intervalo QT prolongado e a hipertrofia cardíaca induzida pelo diabetes. Objetivo: Avaliar os efeitos da TMZ no prolongamento do intervalo QT e na hipertrofia cardíaca em ratos diabéticos. Métodos: Vinte e quatro ratos machos Sprague-Dawley (200-250 g) foram distribuídos aleatoriamente em três grupos (n = 8) pelo método de amostragem aleatória simples. Controle (C), diabético (D) e diabético administrado com TMZ a 10 mg/kg (T10). A TMZ foi administrada por 8 semanas. O ecocardiograma foi registrado antes de isolar os corações e transferir para um aparelho de Langendorff. Foram medidos os parâmetros hemodinâmicos, intervalo QT e intervalo QT corrigido (QTc), frequência cardíaca e enzimas antioxidantes. O índice de hipertrofia foi calculado. Os resultados foram avaliados pelo one-way ANOVA e pelo teste t pareado pelo SPSS (versão 16) e p < 0,05 foi considerado significativo. Resultados: Os ratos diabéticos indicaram hipertrofia aumentada, intervalos QT e QTc e diminuição da pressão sistólica no ventrículo esquerdo (PSVE), pressão desenvolvida no ventrículo esquerdo (PDVE), duplo produto (DP), Max dp/dt e min dp/dt (± dp/dt max), frequência cardíaca, superóxido dismutase (SOD), glutationa peroxidase (GPx) e catalase no coração. O tratamento com TMZ nos animais diabéticos melhorou significativamente esses parâmetros em comparação com o grupo diabético não tratado. Conclusões: A TMZ melhora o prolongamento do intervalo QTc e a hipertrofia cardíaca no diabetes.
Asunto(s)
Animales , Masculino , Trimetazidina/farmacología , Síndrome de QT Prolongado/tratamiento farmacológico , Cardiomegalia/tratamiento farmacológico , Sustancias Protectoras/farmacología , Complicaciones de la Diabetes/tratamiento farmacológico , Superóxido Dismutasa/análisis , Factores de Tiempo , Síndrome de QT Prolongado/enzimología , Síndrome de QT Prolongado/fisiopatología , Ecocardiografía , Catalasa/análisis , Distribución Aleatoria , Reproducibilidad de los Resultados , Ratas Sprague-Dawley , Cardiomegalia/enzimología , Cardiomegalia/etiología , Cardiomegalia/fisiopatología , Complicaciones de la Diabetes/enzimología , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Glutatión Peroxidasa/análisis , Hemodinámica/efectos de los fármacosRESUMEN
BACKGROUND: Trimetazidine (TMZ) is an anti-ischemic drug. In spite of its protective effects on cardiovascular system, there is no scientific study on the usefulness of TMZ treatment for prolonged QT interval and cardiac hypertrophy induced by diabetes. OBJECTIVES: To evaluate the effects of TMZ on QT interval prolongation and cardiac hypertrophy in the diabetic rats. METHODS: Twenty-four male Sprague-Dawley rats (200-250 g) were randomly assigned into three groups (n = 8) by simple random sampling method. Control (C), diabetic (D), and diabetic administrated with TMZ at 10 mg/kg (T10). TMZ was administrated for 8 weeks. The echocardiogram was recorded before isolating the hearts and transfer to a Langendorff apparatus. Hemodynamic parameters, QT and corrected QT interval (QTc) intervals, heart rate and antioxidant enzymes were measured. The hypertrophy index was calculated. The results were evaluated by one-way ANOVA and paired t-test using SPSS (version 16) and p < 0.05 was regarded as significant. RESULTS: The diabetic rats significantly indicated increased hypertrophy, QT and QTc intervals and decreased Left ventricular systolic pressure (LVSP), Left ventricular developed pressure (LVDP), rate pressure product (RPP), Max dp/dt, and min dp/dt (±dp/dt max), heart rate, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase in the heart. Treatment with TMZ in the diabetic animals was significantly improved these parameters in comparison to the untreated diabetic group. CONCLUSIONS: TMZ improves QTc interval prolongation and cardiac hypertrophy in diabetes.
Asunto(s)
Cardiomegalia/tratamiento farmacológico , Complicaciones de la Diabetes/tratamiento farmacológico , Síndrome de QT Prolongado/tratamiento farmacológico , Sustancias Protectoras/farmacología , Trimetazidina/farmacología , Animales , Cardiomegalia/enzimología , Cardiomegalia/etiología , Cardiomegalia/fisiopatología , Catalasa/análisis , Complicaciones de la Diabetes/enzimología , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Ecocardiografía , Glutatión Peroxidasa/análisis , Hemodinámica/efectos de los fármacos , Síndrome de QT Prolongado/enzimología , Síndrome de QT Prolongado/fisiopatología , Masculino , Distribución Aleatoria , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Superóxido Dismutasa/análisis , Factores de TiempoRESUMEN
RATIONALE: Possible beneficial effects of GDF11 (growth differentiation factor 11) on the normal, diseased, and aging heart have been reported, including reversing aging-induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload-induced pathological hypertrophy. OBJECTIVE: To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Twelve- to 13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post-TAC, these mice received rGDF11 (recombinant GDF11) at 1 of 3 doses: 0.5, 1.0, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at 1 week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by heart weight/tibia length ratio, myocyte cross-sectional area, and left ventricular mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0 mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TAC mice. CONCLUSIONS: Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues.
Asunto(s)
Caquexia/etiología , Cardiomegalia/tratamiento farmacológico , Factores de Diferenciación de Crecimiento/uso terapéutico , Animales , Factores de Diferenciación de Crecimiento/administración & dosificación , Factores de Diferenciación de Crecimiento/efectos adversos , Factores de Diferenciación de Crecimiento/farmacología , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismoRESUMEN
Resumen: Objetivo: Determinar algunos mecanismos moleculares por los cuales la activación de ROCK cardíaca post infarto del miocardio (IAM) participa en el remodelado y en deterioro de la función sistólica. Métodos: Determinación simultánea de niveles de proteínas blanco de ROCK cardíaca, de función sistólica in vivo del ventrículo izquierdo (VI) y de fibrosis e hipertrofia cardíaca en ratas con IAM en condiciones de inhibición de ROCK con fasudil. Resultados : Siete días post IAM la masa ventricular relativa aumentó significativamente en un 30% en el grupo MI y se redujo con fasudil. La disfunción sistólica VI mejoró significativamente con fasudil mientras que la activación de ROCK cardíaca se redujo a niveles del grupo control. El inhibidor de ROCK también redujo significativamente los niveles cardíacos elevados de las isoformas ROCK1 y ROCK2, de MHC-β y del colágeno miocárdico. En el grupo con IAM aumentaron significativamente los niveles de fosforilación de ERK 42 y ERK 44 (en 2 veces y en 63%, respectivamente), mientras que en el grupo IAM tratado con fasudil estos niveles fueron similares a los del grupo control. El IAM aumentó significativamente los niveles fosforilados del factor de transcripción GATA-4, que se normalizaron con el inhibidor de ROCK. Conclusiones: La disfunción sistólica post IAM se asoció fuertemente con la activación del ROCK cardíaca y con la fosforilación de proteínas río abajo de ROCK que promueven remodelado cardíaco como β-MHC y la vía ERK / GATA-4.
Abstracts: Objective: to determine some molecular mechanisms by which cardiac ROCK activation after myocardial infarction (MI) intervene in cardiac systolic function decline and remodeling. Methods: simultaneous measurement of different cardiac ROCK target proteins levels, in vivo left ventricular (LV) systolic function, myocardial fibrosis, and hypertrophy in rats with MI under ROCK inhibition with fasudil were performed. Results: seven days after MI the relative ventricular mass increased significantly by 30% in the MI groupand was reduced with fasudil. LV systolic dysfunction improved significantly with fasudil whereas at the same time cardiac ROCK activation was reduced to sham levels. The ROCK inhibitor also reduced increased cardiac levels of both ROCK1 and ROCK2 isoforms, β-MHC levels and myocardial collagen volume fraction decline. MI significantly increased phosphorylation levels of ERK 42 and ERK 44 by 2-fold and 63% respectively whereas in the fasudil-treated MI group these levels were similar to those in the sham group. MI significantly increased phosphorylated levels of the transcription factor GATA-4 which were normalyzed by the ROCK inhibitor. Conclusion: LV systolic dysfunction after MI was strongly associated to cardiac ROCK activation and subsequent phosphorylation of ROCK target proteins that promote ventricular remodeling, such as β-MHC and the ERK/GATA-4 pathway. ROCK inhibition with fasudil significantly improved systolic function, diminished myocardial fibrosis, and normalized β-MHC and ERK/GATA-4 phosphorylation levels.
Asunto(s)
Animales , Ratas , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Inhibidores de Proteínas Quinasas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Infarto del Miocardio/tratamiento farmacológico , Tamaño de los Órganos/efectos de los fármacos , Fosforilación , Western Blotting , Función Ventricular Izquierda/efectos de los fármacos , Ratas Sprague-Dawley , Cardiomegalia/tratamiento farmacológico , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , Remodelación Ventricular/efectos de los fármacos , Modelos Animales de Enfermedad , Infarto del Miocardio/enzimologíaRESUMEN
The renin-angiotensin system (RAS) plays a key role in the control of vasoconstriction as well as sodium and fluid retention mediated mainly by angiotensin (Ang) II acting at the AT1 receptor (AT1R). Ang-(1-7) is another RAS peptide, identified as the endogenous ligand of the Mas receptor and known to counterbalance many of the deleterious effects of AngII. AT1R signaling triggered by ß-arrestin-biased agonists has been associated to cardioprotection. Because position 8 in AngII is important for G protein activation, we hypothesized that Ang-(1-7) could be an endogenous ß-arrestin-biased agonist of the AT1R. Here we show that Ang-(1-7) binds to the AT1R without activating Gq, but triggering ß-arrestins 1 and 2 recruitment and activation. Using an in vivo model of cardiac hypertrophy, we show that Ang-(1-7) significantly attenuates heart hypertrophy by reducing both heart weight and ventricular wall thickness and the increased end-diastolic pressure. Whereas neither the single blockade of AT1 or Mas receptors with their respective antagonists prevented the cardioprotective action of Ang1-7, combination of the two antagonists partially impaired the effect of Ang-(1-7). Taken together, these data indicate that Ang-(1-7) mediates at least part of its cardioprotective effects by acting as an endogenous ß-arrestin-biased agonist at the AT1R.
Asunto(s)
Angiotensina I/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Receptor de Angiotensina Tipo 1/metabolismo , beta-Arrestinas/agonistas , Angiotensina I/metabolismo , Animales , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Cardiotónicos/metabolismo , Diástole/efectos de los fármacos , Células HEK293 , Corazón/efectos de los fármacos , Corazón/fisiopatología , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fragmentos de Péptidos/metabolismo , Fosforilación , Ratas , Ratas Endogámicas WF , Transducción de Señal/efectos de los fármacos , beta-Arrestinas/metabolismoRESUMEN
Pathological cardiac hypertrophy is characterized by wall thickening or chamber enlargement of the heart in response to pressure or volume overload, respectively. This condition will, initially, improve the organ contractile function, but if sustained will render dysfunctional mitochondria and oxidative stress. Mitochondrial ATP-sensitive K+ channels (mitoKATP) modulate the redox status of the cell and protect against several cardiac insults. Here, we tested the hypothesis that mitoKATP opening (using diazoxide) will avoid isoproterenol-induced cardiac hypertrophy in vivo by decreasing reactive oxygen species (ROS) production and mitochondrial Ca2+-induced swelling. To induce cardiac hypertrophy, Swiss mice were treated intraperitoneally with isoproterenol (30 mg/kg/day) for 8 days. Diazoxide (5 mg/kg/day) was used to open mitoKATP and 5-hydroxydecanoate (5 mg/kg/day) was administrated as a mitoKATP blocker. Isoproterenol-treated mice had elevated heart weight/tibia length ratios and increased myocyte cross-sectional areas. Additionally, hypertrophic hearts produced higher levels of H2O2 and had lower glutathione peroxidase activity. In contrast, mitoKATP opening with diazoxide blocked all isoproterenol effects in a manner reversed by 5-hydroxydecanoate. Isolated mitochondria from Isoproterenol-induced hypertrophic hearts had increased susceptibility to Ca2+-induced swelling secondary to mitochondrial permeability transition pore opening. MitokATP opening was accompanied by lower Ca2+-induced mitochondrial swelling, an effect blocked by 5-hydroxydecanoate. Our results suggest that mitoKATP opening negatively regulates cardiac hypertrophy by avoiding oxidative impairment and mitochondrial damage.