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1.
Am J Physiol Renal Physiol ; 318(2): F388-F401, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841388

RESUMO

Cardiovascular disease (CVD) is the main cause of death in patients with kidney disease. Hypoxia plays a crucial role in the progression of chronic kidney disease (CKD) and cardiovascular disease, which is associated with fibrosis, inflammation, and oxidative injury. Previous studies have indicated that prolyl hydroxylase (PHD) inhibitors, stabilizers of hypoxia-inducible factors (HIFs), can be used to treat acute organ injuries such as renal ischemia-reperfusion, myocardial infarction, and, in some contexts, CKD. However, the effects of PHD inhibitors on cardiovascular complications in CKD remain unknown. In the present study, we investigated whether HIF activation has a beneficial effect on kidney and cardiovascular outcomes in the remnant kidney model. We used the 5/6 nephrectomy model with the nitric oxide synthase inhibitor Nω-nitro-l-arginine (20 mg/L in the drinking water). Rats received diet with 0.005% enarodustat (PHD inhibitor) or vehicle for 8 wk starting 2 wk before 5/6 nephrectomy. Activation of HIF by the PHD inhibitor reduced cardiac hypertrophy and ameliorated myocardial fibrosis in association with restored capillary density and improvement in mitochondrial morphology. With regard to kidneys, enarodustat ameliorated fibrosis in association with reduced proinflammatory cytokine expression, reduced apoptosis, and restored capillary density, even though renal endpoints such as proteinuria and serum creatinine levels were not significantly affected by enarodustat, except for blood urea nitrogen levels at 4 wk. In addition, cardiac hypertrophy marker genes, including atrial natriuretic peptide, were suppressed in P19CL6 cells treated with enarodustat. These findings suggest that PHD inhibitors might show beneficial effects in cardiovascular complications caused by CKD.


Assuntos
Hipertrofia Ventricular Esquerda/prevenção & controle , Rim/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Glicinas N-Substituídas/farmacologia , Prolil Hidroxilases/metabolismo , Inibidores de Prolil-Hidrolase/farmacologia , Piridinas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mediadores da Inflamação/metabolismo , Rim/enzimologia , Rim/patologia , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/enzimologia , Mitocôndrias Cardíacas/ultraestrutura , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/ultraestrutura , Neovascularização Fisiológica/efeitos dos fármacos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
2.
Hypertension ; 74(4): 843-853, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476902

RESUMO

Preterm birth is associated with proinflammatory conditions and alterations in adult cardiac shape and function. Neonatal exposure to high oxygen, a rat model of prematurity-related conditions, leads to cardiac remodeling, fibrosis, and dysfunction. TLR (Toll-like receptor) 4 signaling is a critical link between oxidative stress, inflammation, and the pathogenesis of cardiovascular diseases. The current study sought to investigate the role of TLR4 signaling in neonatal oxygen-induced cardiomyopathy. Male Sprague-Dawley pups were kept in 80% oxygen or room air from day 3 to 10 of life and treated with TLR4 antagonist lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides(LPS-RS) or saline. Echocardiography was performed at 4, 7, and 12 weeks. At 12 weeks, intraarterial blood pressure was measured before euthanization for histological and biochemical analyses. At day 10, cardiac TLR4, Il (interleukin) 18, and Il1ß expression were increased in oxygen-exposed compared with room air controls. At 4 weeks, compared with room air-saline, saline-, but not LPS-RS treated-, oxygen-exposed animals, exhibited increased left ventricle mass index, reduced ejection fraction, and cardiac output index. Findings were similar at 7 and 12 weeks. LPS-RS did not influence echocardiography in 12 weeks room air animals. Systolic blood pressure was higher in saline- but not LPS-RS treated-oxygen-exposed animals compared with room air-saline and -LPS-RS controls. LPS-RS prevented cardiac fibrosis and cardiomyocytes hypertrophy, the increased TLR4, Myd88, and Il18 gene expression, TRIF expression, and CD68+ macrophages infiltration associated with neonatal oxygen exposure, without impact in room air rats. This study indicates that neonatal exposure to high oxygen programs TLR4 activation, which contributes to cardiac remodeling and dysfunction.


Assuntos
Hiperóxia/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Lipopolissacarídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Animais Recém-Nascidos , Citocinas/metabolismo , Modelos Animais de Doenças , Hiperóxia/complicações , Hiperóxia/metabolismo , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle
3.
Hum Exp Toxicol ; 38(10): 1183-1194, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31256679

RESUMO

Heart failure (HF) is a leading cause of hospitalization across the world and is known to cause ill-health and heavy economic losses. In the present study, a rat model of isoproterenol (ISO, 85 mg/kg subcutaneously for two subsequent days) induced HF was developed. ISO induces HF by its direct effect, that is, rise in left ventricular end-diastolic pressure (mechanical) and indirectly by altering the baroreflex (neural), electrocardiography (electrical), and development of oxidative stress and hyperlipidemia (chemical). Fenofibrate, a hypolipidemic drug, which ameliorates myocardial energy metabolism was seen to improve the both ISO-induced oxidative stress and lipid profile and consequently improved Baroreflex Sensitivity (BRS), partial ventricular functions, and cardiac hypertrophy. Therefore, our result suggests that fenofibrate treatment protected the heart by alleviating the ISO-induced effects, that is, neural, mechanical, electrical, and chemical alterations.


Assuntos
Barorreflexo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Fenofibrato/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipolipemiantes/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Eletrocardiografia/efeitos dos fármacos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , NADPH Oxidases/genética , Ratos Wistar
4.
Nutrients ; 11(8)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357464

RESUMO

Olive oil and its derivatives have been described to exert beneficial effects on hypertensive states and cardiovascular disease prevention. We studied the effects of chronic consumption of extra virgin olive oil (EVOO), enriched in bioactive compounds from olive fruit and leaves, on blood pressure, endothelial function, oxidative and inflammatory status, and circulating cholesterol levels, in spontaneously hypertensive rats (SHR). Thirty SHR were randomly assigned to three groups: a control untreated SHR group, an SHR group (1 mL/rat/day) of a control olive oil (17.6 mg/kg of phenolic compounds), and an SHR group (1 mL/rat/day) of the enriched EVOO (750 mg/kg of phenolic compounds) for eight weeks. Ten Wistar Kyoto rats (WKY) were included as healthy controls. Long-term administration of the enriched EVOO decreased systolic blood pressure and cardiac hypertrophy, and improved the ex vivo aortic endothelial dysfunction measured in SHR. Moreover, enriched oil supplementation reduced the plasma levels of Angiotensin II and total cholesterol, and the urinary levels of endothelin-1 and oxidative stress biomarkers, while pro-inflammatory cytokines were unaffected. In conclusion, sustained treatment with EVOO, enriched in bioactive compounds from the olive fruit and leaves, may be an effective tool for reducing blood pressure and cholesterol levels alone or in combination with pharmacological anti-hypertensive treatment.


Assuntos
Suplementos Nutricionais , Alimentos Fortificados , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Azeite de Oliva/administração & dosagem , Animais , Biomarcadores/sangue , Pressão Sanguínea , Colesterol/sangue , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/fisiopatologia , Mediadores da Inflamação/sangue , Masculino , Estresse Oxidativo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasodilatação , Função Ventricular Esquerda , Remodelação Ventricular
5.
Life Sci ; 230: 19-27, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125563

RESUMO

AIMS: We investigated the effect of the selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin on cardiac dysfunction and histopathology in a non-diabetic rat model of cardiomyopathy. MAIN METHODS: Ipragliflozin was mixed with chow (0.01%, w/w) and administered to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 8 weeks. Male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats of the same age were used as controls. Systolic blood pressure (SBP) and heart rate (HR) were measured every 4 weeks. After 8 weeks of treatment, echocardiography and histopathological examinations were performed. Further, the effect of ipragliflozin on blood and urine parameters were investigated. KEY FINDINGS: In the DS/obese rats, ipragliflozin delayed the age-related increase in SBP without affecting HR, reduced left ventricular (LV) mass and intraventricular septal thickness in echocardiography, and ameliorated hypertrophy of cardiomyocytes and LV fibrosis in histopathological examination. Although ipragliflozin significantly increased both urine volume and urinary glucose excretion in DS/obese rats, it did not alter plasma glucose levels. SIGNIFICANCE: Ipragliflozin prevented LV hypertrophy and fibrosis in non-diabetic DS/obese rats without affecting plasma glucose levels. These findings suggest that SGLT2 inhibitors have a cardio-protective effect in non-diabetic patients with cardiomyopathy.


Assuntos
Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/patologia , Glucosídeos/farmacologia , Tiofenos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Ecocardiografia , Fibrose/tratamento farmacológico , Fibrose/prevenção & controle , Glucosídeos/metabolismo , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/prevenção & controle , Hipoglicemiantes/farmacologia , Masculino , Síndrome Metabólica/fisiopatologia , Obesidade , Ratos , Ratos Endogâmicos Dahl , Transportador 2 de Glucose-Sódio/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sístole/efeitos dos fármacos , Tiofenos/metabolismo
6.
Cardiovasc Toxicol ; 19(1): 72-81, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30128816

RESUMO

Heart failure-associated morbidity and mortality is largely attributable to extensive and unregulated cardiac remodelling. Roselle (Hibiscus sabdariffa) calyces are enriched with natural polyphenols known for antioxidant and anti-hypertensive effects, yet its effects on early cardiac remodelling in post myocardial infarction (MI) setting are still unclear. Thus, the aim of this study was to investigate the actions of roselle extract on cardiac remodelling in rat model of MI. Male Wistar rats (200-300 g) were randomly allotted into three groups: Control, MI, and MI + Roselle. MI was induced with isoprenaline (ISO) (85 mg/kg, s.c) for two consecutive days followed by roselle treatment (100 mg/kg, orally) for 7 days. Isoprenaline administration showed changes in heart weight to body weight (HW/BW) ratio. MI was especially evident by the elevated cardiac injury marker, troponin-T, and histological observation. Upregulation of plasma levels and cardiac gene expression levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 was seen in MI rats. A relatively high percentage of fibrosis was observed in rat heart tissues with over-expression of collagen (Col)-1 and Col-3 genes following isoprenaline-induced MI. On top of that, cardiomyocyte areas were larger in heart tissues of MI rats with upregulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression, indicating cardiac hypertrophy. Interestingly, roselle supplementation attenuated elevation of plasma troponin-T, IL-6, IL10, and gene expression level of IL-10. Furthermore, reduction of cardiac fibrosis and hypertrophy were observed. In conclusion, roselle treatment was able to limit early cardiac remodelling in MI rat model by alleviating inflammation, fibrosis, and hypertrophy; hence, the potential application of roselle in early adjunctive treatment to prevent heart failure.


Assuntos
Fármacos Cardiovasculares/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Hibiscus , Hipertrofia Ventricular Esquerda/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Fármacos Cardiovasculares/isolamento & purificação , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Modelos Animais de Doenças , Fibrose , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hibiscus/química , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-6/sangue , Interleucina-6/genética , Isoproterenol , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos Wistar , Troponina T/sangue
7.
Mol Cell Biochem ; 450(1-2): 25-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29790114

RESUMO

This study aimed to investigate the effects and molecular mechanisms of ivabradine in preventing cardiac hypertrophy in an established transverse aortic constriction (TAC) mouse model. A total of 56 male C57BL/6 mice were randomly assigned into the following seven groups (8 mice per group): sham, TAC model, Iva-10 (10 mg/kg/day ivabradine), Iva-20 (20 mg/kg/day ivabradine), Iva-40 (40 mg/kg/day ivabradine), Iva-80 (80 mg/kg/day ivabradine), and Rap (rapamycin, a positive control). Echocardiography and left ventricular hemodynamics were performed. Hematoxylin-eosin (H&E), Masson's trichome staining, and TUNEL assays were conducted to evaluate cardiac hypertrophy, fibrosis, and apoptosis, respectively. Western blotting was performed to detect the expression of proteins related to the PI3K/Akt/mTOR/p70S6K pathway. Ivabradine could effectively improve left ventricular dysfunction and hypertrophy induced by TAC in a dose-independent manner. Moreover, no obvious change in heart rate (HR) was observed in the TAC and Rap groups, whereas a significant decrease in HR was found after ivabradine treatment (P < 0.05). Cardiac hypertrophy, fibrosis, and apoptosis induced by TAC were notably suppressed after either rapamycin or ivabradine treatment (P < 0.05). Ivabradine and rapamycin also decreased the expression of PI3K/Akt and mTOR induced by TAC. Ivabradine improved cardiac hypertrophy and fibrosis as well as reduced cardiomyocyte apoptosis via the PI3K/Akt/mTOR/p70S6K pathway in TAC model mice.


Assuntos
Doenças da Aorta/fisiopatologia , Apoptose , Constrição Patológica/fisiopatologia , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/prevenção & controle , Ivabradina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Fármacos Cardiovasculares/farmacologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Pressão , Disfunção Ventricular Esquerda/patologia
8.
Clin Exp Hypertens ; 41(4): 307-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29902079

RESUMO

PURPOSE: Hypertension is an important risk factor for death resulting from stroke, myocardial infarction, and end-stage renal failure. Hydrogen (H2) gas protects against many diseases, including ischemia-reperfusion injury and stroke. The effects of H2 on hypertension and its related left ventricular (LV) function have not been fully elucidated. The purpose of this study was to investigate the effects of H2 gas on hypertension and LV hypertrophy using echocardiography. METHODS: Dahl salt-sensitive (DS) rats were randomly divided into three groups: those fed an 8% NaCl diet until 12 weeks of age (8% NaCl group), those additionally treated with 2% H2 gas (8% NaCl + 2% H2 group), and control rats maintained on a diet containing 0.3% NaCl until 12 weeks of age (0.3% NaCl group). H2 gas was supplied through a gas flowmeter and delivered by room air (2% hydrogenated room air, flow rate of 10 L/min) into a cage surrounded by an acrylic chamber. We evaluated interventricular septal wall thickness (IVST), LV posterior wall thickness (LVPWT), and LV mass using echocardiography. RESULTS: IVST, LVPWT, and LV mass were significantly higher in the 8% NaCl group than the 0.3% NaCl group at 12 weeks of age, whereas they were significantly lower in the 8% NaCl + 2% H2 group than the 8% NaCl group. There was no significant difference in systolic blood pressure between the two groups. CONCLUSION: Our findings suggest that chronic H2 gas inhalation may help prevent LV hypertrophy in hypertensive DS rats.


Assuntos
Gases/uso terapêutico , Hidrogênio/uso terapêutico , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Animais , Pressão Sanguínea/efeitos dos fármacos , Ecocardiografia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Ratos , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos
9.
Cardiovasc Diabetol ; 17(1): 160, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591063

RESUMO

BACKGROUND: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. METHODS: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-ß1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. RESULTS: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. CONCLUSIONS: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Piperidinas/farmacologia , Uracila/análogos & derivados , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diástole/efeitos dos fármacos , Fibrose , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Fator 1 Nuclear Respiratório/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Uracila/farmacologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
10.
PLoS One ; 13(12): e0207844, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30576317

RESUMO

Dysregulation of the renin-angiotensin system leads to systemic hypertension and maladaptive fibrosis in various organs. We showed recently that myocardial fibrosis and the loss of cardiac function in mice with transverse aortic constriction (TAC) could be averted by treatment with the caveolin-1 scaffolding domain (CSD) peptide. Here, we used angiotensin II (AngII) infusion (2.1 mg/kg/day for 2 wk) in mice as a second model to confirm and extend our observations on the beneficial effects of CSD on heart and kidney disease. AngII caused cardiac hypertrophy (increased heart weight to body weight ratio (HW/BW) and cardiomyocyte cross-sectional area); fibrosis in heart and kidney (increased levels of collagen I and heat shock protein-47 (HSP47)); and vascular leakage (increased levels of IgG in heart and kidney). Echocardiograms of AngII-infused mice showed increased left ventricular posterior wall thickness (pWTh) and isovolumic relaxation time (IVRT), and decreased ejection fraction (EF), stroke volume (SV), and cardiac output (CO). CSD treatment (i.p. injections, 50 µg/mouse/day) of AngII-infused mice significantly suppressed all of these pathological changes in fibrosis, hypertrophy, vascular leakage, and ventricular function. AngII infusion increased ß1 and ß3 integrin levels and activated Pyk2 in both heart and kidney. These changes were also suppressed by CSD. Finally, bone marrow cell (BMC) isolated from AngII-infused mice showed hyper-migration toward SDF1. When AngII-infused mice were treated with CSD, BMC migration was reduced to the basal level observed in cells from control mice. Importantly, CSD did not affect the AngII-induced increase in blood pressure (BP), indicating that the beneficial effects of CSD were not mediated via normalization of BP. These results strongly indicate that CSD suppresses AngII-induced pathological changes in mice, suggesting that CSD can be developed as a treatment for patients with hypertension and pressure overload-induced heart failure.


Assuntos
Angiotensina II/administração & dosagem , Caveolina 1/administração & dosagem , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Miocárdio/patologia , Fragmentos de Peptídeos/administração & dosagem , Angiotensina II/fisiologia , Angiotensinas/antagonistas & inibidores , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/fisiologia , Permeabilidade Capilar/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Fibrose/etiologia , Fibrose/patologia , Fibrose/prevenção & controle , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Transdução de Sinais/efeitos dos fármacos
11.
J Clin Hypertens (Greenwich) ; 20(10): 1507-1515, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30251403

RESUMO

Left ventricular hypertrophy develops in 36%-41% of hypertensive patients and independently predicts cardiovascular events and total mortality. Moreover, drug-induced reduction in left ventricular mass (LVM) correlates with improved prognosis. The optimal thiazide-type diuretic for reducing LVM is unknown. Evidence regarding potency, cardiovascular events, sodium, and potassium suggested the hypothesis that "CHIP" diuretics (CHlorthalidone, Indapamide, and Potassium-sparing diuretic/hydrochlorothiazide [PSD/HCTZ]) would reduce LVM more than HCTZ. Systematic searches of five databases were conducted. Among the 38 randomized trials, a 1% reduction in systolic blood pressure (SBP) predicted a 1% reduction in LVM, P = 0.00001. CHIP-HCTZ differences in reducing LVM differed across trials (ie, heterogeneity), making interpretation uncertain. However, among the 28 double-blind trials, heterogeneity was undetectable, and HCTZ reduced LVM (percent reduction [95% CI]) by -7.3 (-10.4, -4.2), P < 0.0001. CHIP diuretics surpassed HCTZ in reducing LVM: chlorthalidone -8.2 (-14.7, -1.6), P = 0.015; indapamide -7.5 (-12.7, -2.3), P = 0.005; and all CHIP diuretics combined -7.7 (-12.2, -3.1), P < 0.001. The comparison of PSD/HCTZ with HCTZ had low statistical power but favored PSD/HCTZ: -6.0 (-14.1, +2.1), P = 0.149. Thus, compared to HCTZ, CHIP diuretics had twice the effect on LVM. CHIP diuretics did not surpass HCTZ in reducing systolic or diastolic blood pressure: -0.3 (-5.0, +4.3) and -1.6 (-5.6, +2.4), respectively. The strength of evidence that CHIP diuretics surpass HCTZ for reducing LVM was high (GRADE criteria). In conclusion, these novel results have demonstrated that CHIP diuretics reduce LVM 2-fold more than HCTZ among hypertensive patients. Although generally related to LVM, blood pressure fails to explain the superiority of CHIP diuretics for reducing LVM.


Assuntos
Clortalidona/farmacologia , Diurético Poupador de Potássio/farmacologia , Hidroclorotiazida/farmacologia , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Indapamida/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/administração & dosagem , Clortalidona/uso terapêutico , Diurético Poupador de Potássio/administração & dosagem , Diurético Poupador de Potássio/uso terapêutico , Quimioterapia Combinada/métodos , Feminino , Humanos , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/uso terapêutico , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Indapamida/administração & dosagem , Indapamida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Tiazidas/farmacologia , Tiazidas/uso terapêutico
13.
Biomed Pharmacother ; 106: 1390-1395, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119211

RESUMO

Left ventricular hypertrophy (LVH) is a pathological characteristic shared by distinct heart disorders. Atorvastatin is employed as a lipid lowering agent and its heart protection effect has been recently reported as well. Thus, the current study attempted to validate the anti-hypertrophy effect of atorvastatin as well as the associated mechanism. Hypertrophic feature was induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using angiotensin II (Ang II). Then the animals and cells were treated with atorvastatin and the effect on cardiac weight and structure as well as cell viability, surface area, and apoptosis was assessed. The mechanism associated with the anti-hypertrophy effect of atorvastatin was further explored by focusing on the AMPK/Foxo1/miR-143-3p axis. The results showed that the administration of atorvastatin significantly suppressed TAC-induced heart weight increase and attenuated cardiac structure deteriorations in rats. In in vitro assays, atorvastatin increased cell viability, and reduced cell surface area and apoptosis in Ang II-treated H9c2 cells. At molecular level, atorvastatin activated AMPK, which further promoted Foxo1 activation and suppressed miR-143-3p level. The key role of AMPK during atorvastatin treatment was further validated by subjecting Ang II-treated H9c2 cells to co-incubation of atorvastatin and Compound C, which blocked the pro-survival and anti-hypertrophy effect of atorvastatin on H9c2 cells. The findings outlined in the current study confirmed the anti-hypertrophy effect of atorvastatin and provided a preliminary explanation on the mechanism associated with the treatment: the protective effect of atorvastatin on myocardium against hypertrophy depended on miR-143-3p inhibition via AMPK and Foxo1 activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Atorvastatina/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Angiotensina II/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Masculino , MicroRNAs/genética , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
14.
Pharmacol Res ; 134: 193-199, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29959031

RESUMO

The reduction of echocardiographic left ventricular (LV) mass and the change toward a less concentric geometry during antihypertensive treatment are independently associated with a better prognosis. Blood pressure-lowering treatment may reduce cardiac hypertrophy, although different effect on changes of LV mass have been reported among antihypertensive drug classes, while changes in echocardiographic evaluated LV geometry have not been systemically evaluated. It is not yet clear whether antihypertensive drugs may influence LV geometry. Our aim was to compare the effects of diuretics (D), beta-blockers (BB), calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACE-I), and angiotensin receptor blockers (ARBS) on relative wall thickness (RWT) in patients with hypertension on the basis of prospective, randomized comparative studies. METHODS: MEDLINE, and the ISI Web of Sciences were searched for randomized clinical trials evaluating LV mass and geometry at baseline and end follow-up. We have performed a pooled pairwise comparisons of the effect of the 5 major drug classes on relative wall thickness changes, and of each drug class versus other classes statistically combined. RESULTS: We selected 53 publications involving 7684 patients. A significant correlation was observed between percent changes from baseline to end of treatment in LV mass and those in systolic BP (r = 0.44, p < 0.001). Reduction of LV mass was significantly greater with CCB than with BB (P <  0.02) without other significant differences between drug classes. Percent changes in RWT were related to percent changes in LV mass/LVmass index (r = 0.68, p = 0.016) and of SBP (r = 0.64 p < 0.033). RWT decreased during treatment with all classes of drugs, except the combination of BB and D; the decrease of RWT was less with diuretics and sympatholytic drugs. CONCLUSIONS: In studies evaluating the effect of different classes of antihypertensive drugs on LV mass, the reduction of relative wall thickness seems to be less during treatment with diuretics.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Adulto , Idoso , Feminino , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do Tratamento
15.
J Am Heart Assoc ; 7(12)2018 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-29887522

RESUMO

BACKGROUND: The insulin/insulin-like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin-2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin-like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss-of-function and protein delivery methods. METHODS AND RESULTS: Insl6-deficient and wild-type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6-knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6-knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis-associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol-challenged hearts treated with INSL6 protein. CONCLUSIONS: Endogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II- and isoproterenol-induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis.


Assuntos
Insuficiência Cardíaca/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/patologia , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Transdução de Sinais , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
16.
J Am Heart Assoc ; 7(13)2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29945911

RESUMO

BACKGROUND: Carboxyl-terminal modulator protein (CTMP) has been implicated in cancer, brain injury, and obesity. However, the role of CTMP in pathological cardiac hypertrophy has not been identified. METHODS AND RESULTS: In this study, decreased expression of CTMP was observed in both human failing hearts and murine hypertrophied hearts. To further explore the potential involvement of CTMP in pathological cardiac hypertrophy, cardiac-specific CTMP knockout and overexpression mice were generated. In vivo experiments revealed that CTMP deficiency exacerbated the cardiac hypertrophy, fibrosis, and function induced by pressure overload, whereas CTMP overexpression alleviated the response to hypertrophic stimuli. Consistent with the in vivo results, adenovirus-mediated gain-of-function or loss-of-function experiments showed that CTMP also exerted a protective effect against hypertrophic responses to angiotensin II in vitro. Mechanistically, CTMP ameliorated pathological cardiac hypertrophy through the blockade of the protein kinase B signaling pathway. Moreover, inhibition of protein kinase B activation with LY294002 rescued the deteriorated effect in aortic banding-treated cardiac-specific CTMP knockout mice. CONCLUSIONS: Taken together, these findings imply, for the first time, that increasing the cardiac expression of CTMP may be a novel therapeutic strategy for pathological cardiac hypertrophy.


Assuntos
Proteínas de Transporte/metabolismo , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Função Ventricular Esquerda , Remodelação Ventricular , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos Knockout , Miócitos Cardíacos/patologia , Palmitoil-CoA Hidrolase , Ratos Sprague-Dawley , Transdução de Sinais , Tioléster Hidrolases/metabolismo
17.
Pediatr Nephrol ; 33(9): 1585-1591, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29766272

RESUMO

BACKGROUND: There is no detailed strain analysis of cardiac functions in treated hypertensive pediatric patients. The aim of this study was to evaluate the cardio-protective effects of different drug classes in treated pediatric hypertensive patients. METHODS: Sixty non-obese-treated hypertensive patients with preserved left ventricular (LV) systolic function and 45 age-, sex-, and body mass index-matched healthy subjects underwent clinical evaluation, including 24-h ambulatory blood pressure monitoring, standard echocardiographic examination, tissue Doppler imaging, and two-dimensional Speckle Tracking Echocardiography. The patients were divided into two subgroups based on the effects of the drugs on the Renin Angiotensin Aldosterone System. The subgroup hypertension (HT) 1 received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and HT 2 subgroup received calcium channel blocker, ß-blocker, or diuretics. RESULTS: There was no difference between the two groups and subgroups with respect to clinical, demographic, ABPM, ventricular volumes, ejection fraction, and tissue Doppler imaging (TDI) parameters. For patients and controls, respectively, global longitudinal strain was - 18.70 ± 3.41 versus - 21.01 ± 3.82 (P < 0.001), and global radial strain was 40.6 ± 9.8 versus 54.8 ± 12.8 (P = 0.004). Peak LV twist and peak LV torsion were not significantly different. The patient subgroup analyses with each other revealed no difference in systolic and diastolic myocardial deformation properties. CONCLUSIONS: Strain parameters were reduced in all treated hypertensive children compared to normotensive children, and the various cardiac mechanic parameters were similarly abnormal no matter what type of antihypertensive agent was used.


Assuntos
Anti-Hipertensivos/uso terapêutico , Ventrículos do Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Adolescente , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Criança , Ecocardiografia Doppler , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle
18.
Cardiovasc Res ; 114(12): 1629-1641, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800064

RESUMO

Aims: Transforming growth factor ß1 (TGF-ß1) is a prosclerotic cytokine involved in cardiac remodelling leading to heart failure (HF). Acetylation/de-acetylation of specific lysine residues in Smad2/3 has been shown to regulate TGF-ß signalling by altering its transcriptional activity. Recently, the lysine de-acetylase sirtuin 1 (SIRT1) has been shown to have a cardioprotective effect; however, SIRT1 expression and activity are paradoxically reduced in HF. Herein, we investigate whether pharmacological activation of SIRT1 would induce cardioprotection in a pressure overload model and assess the impact of SIRT1 activation on TGF-ß signalling and the fibrotic response. Methods and results: Eight weeks old male C57BL/6 mice were randomized to undergo sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Post-surgery, animals were further randomized to receive SRT1720 or vehicle treatment. Echocardiography, pressure-volume loops, and histological analysis revealed an impairment in cardiac function and deleterious left ventricular remodelling in TAC-operated animals that was improved with SRT1720 treatment. Genetic ablation and cell culture studies using a Smad-binding response element revealed SIRT1 to be a specific target of SRT1720 and identified Smad2/3 as a SIRT1 specific substrate. Conclusion: Overall, our data demonstrate that Smad2/3 is a specific SIRT1 target and suggests that pharmacological activation of SIRT1 may be a novel therapeutic strategy to prevent/reverse HF via modifying Smad activity.


Assuntos
Ativadores de Enzimas/farmacologia , Insuficiência Cardíaca/prevenção & controle , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Acetilação , Animais , Células Cultivadas , Modelos Animais de Doenças , Ativação Enzimática , Fibrose , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Histonas/metabolismo , Humanos , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fosforilação , Processamento de Proteína Pós-Traducional , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/genética , Fator de Crescimento Transformador beta/metabolismo
19.
J Cardiovasc Pharmacol ; 72(1): 40-48, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29688911

RESUMO

Tranilast is clinically indicated for the treatment of allergic disorders and is also a nonselective blocker of the transient receptor potential vanilloid 2 (TRPV2) channel. Previous studies have found that it has protective effects in various animal models of cardiac disease. Our laboratory has found that genetic deletion of TRPV2 results in a blunted hypertrophic response to increased afterload; thus, this study tested the hypothesis that tranilast through cardiomyocyte TRPV2 blockade can inhibit the hypertrophic response to pressure overload in vivo through transverse aortic constriction and ex vivo through isolated myocyte studies. The in vivo studies demonstrated that tranilast blunted the fibrotic response to increased afterload and, to a lesser extent, the hypertrophic response. After 4 weeks, this blunting was associated with improved cardiac function, although at 8 weeks, the cardiac function deteriorated similarly to the control group. Finally, the in vitro studies demonstrated that tranilast was not inhibiting these responses at the cardiomyocyte level. In conclusion, we demonstrated that tranilast blunting of the fibrotic and hypertrophic response occurs independently of cardiac TRPV2 channels and may be cardioprotective in the short term but not after prolonged administration.


Assuntos
Hipertrofia Ventricular Esquerda/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Recuperação de Função Fisiológica , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , ortoaminobenzoatos/toxicidade
20.
J Cardiovasc Pharmacol Ther ; 23(4): 358-371, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29627992

RESUMO

The effectiveness of empagliflozin (EMPA), a sodium glucose cotransporter type 2 inhibitor, on the kidney, pancreas, and heart was investigated in the Cohen Rosenthal diabetic hypertensive rat model (CRDH rat). Six-week-old CRDH male rats were fed a sugar diet (SD) and treated with the compound EMPA (group Drug/SD) or respective comparator with vehicle (group Veh/SD). A control group was fed a regular diet without treatment (group Veh/P). Preventive treatment with EMPA was measured during 4 months of follow-up. The treatment effect was evaluated according to results observed after 4 months in group Drug/SD when compared to those in group Veh/SD. Significant effect resulted in the following parameters: enhancement of urinary glucose excretion in association with diuresis; amelioration of postprandial hyperglycemia and fasting blood glucose levels; and decrease in calculated Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) as well as lower systolic and diastolic blood pressures. At the end of treatment, EMPA preserved nephrin integrity in the kidney, reduced proteinuria, and prevented diabetes-induced damage to glomerular diaphragm structure. In the pancreas, EMPA demonstrated an impressive decrease in fatty infiltration and atrophy. Blood pressure was significantly reduced in the EMPA-treated group (15 ± 5.1 mm Hg, P < .05) in contrast to the vehicle and control groups. Finally, compared to controls, EMPA significantly reduced left ventricle (LV) mass and LV systolic dilatation, according to 2-dimensional echocardiography. The importance of the study lies in demonstrating the efficacy of an antidiabetic drug with beneficial effects on blood pressure, weight, kidney, and pancreas and a positive effect on the heart.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Glucosídeos/farmacologia , Hipertensão/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Homeostase , Hipertensão/sangue , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Resistência à Insulina , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Proteinúria/sangue , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Ratos Endogâmicos SHR , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle
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