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1.
Cardiovasc Diabetol ; 18(1): 45, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935417

RESUMO

BACKGROUND: Sodium glucose co-transporter 2 inhibitor (SGLT2i), a new class of anti-diabetic drugs acting on inhibiting glucose resorption by kidneys, is shown beneficial in reduction of heart failure hospitalization and cardiovascular mortality. The mechanisms remain unclear. We hypothesized that SGLT2i, empagliflozin can improve cardiac hemodynamics in non-diabetic hypertensive heart failure. METHODS AND RESULTS: The hypertensive heart failure model had been created by feeding spontaneous hypertensive rats (SHR) with high fat diet for 32 weeks (total n = 13). Half SHRs were randomized to be administered with SGLT2i, empagliflozin at 20 mg/kg/day for 12 weeks. After evaluation of electrocardiography and echocardiography, invasive hemodynamic study was performed and followed by blood sample collection and tissue analyses. Empagliflozin exhibited cardiac (improved atrial and ventricular remodeling) and renal protection, while plasma glucose level was not affected. Empagliflozin normalized both end-systolic and end-diastolic volume in SHR, in parallel with parameters in echocardiographic evaluation. Empagliflozin also normalized systolic dysfunction, in terms of the reduced maximal velocity of pressure incline and the slope of end-systolic pressure volume relationship in SHR. In histological analysis, empagliflozin significantly attenuated cardiac fibrosis in both atrial and ventricular tissues. The upregulation of atrial and ventricular expression of PPARα, ACADM, natriuretic peptides (NPPA and NPPB), and TNF-α in SHR, was all restored by treatment of empagliflozin. CONCLUSIONS: Empagliflozin improves hemodynamics in our hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes. Our results contribute some understanding of the pleiotropic effects of empagliflozin on improving heart function.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Hipertensão/complicações , Miocárdio/patologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Função do Átrio Esquerdo/efeitos dos fármacos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fibrose , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Masculino , Miocárdio/metabolismo , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Encefálico/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Recuperação de Função Fisiológica , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Medicine (Baltimore) ; 98(17): e15277, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31027084

RESUMO

There exists controversy on whether and for how long anticoagulation is necessary after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).We aimed to study the impact of prolonged (>24 h) or brief (<24 h) postprocedural anticoagulation on infarct size assessed by cardiac magnetic resonance (CMR) after 30 days as well as on left ventricular ejection fraction (LVEF) and left ventricular (LV) remodeling evaluated by 2D-echocardiography after 9 months from the INNOVATION trial (Clinical Trial Registration: NCT02324348).Of the 114 patients (mean age: 59.5 years) enrolled, 76 (66.7%) received prolonged anticoagulation therapy (median duration: 72.6 h) and 38 (33.3%) patients received brief anticoagulation therapy (median duration: 5 h) after primary PCI. There was no significant difference in infarct size (mean size: 15.6% after prolonged anticoagulation versus 19.8% after brief anticoagulation, P = .100) and the incidence of microvascular obstruction (50.7% versus 52.9%, P = .830) between the groups. Even after adjusting, prolonged anticoagulation therapy could not reduce larger infarct (defined as >75 percentile of infarct size; 19.7% versus 35.3%; adjusted odd ratio [OR]: 0.435; 95% confidence interval [CI]: 0.120-1.57; P = .204). Similar results were observed in subanalyses of major high-risk subgroups. Moreover, follow-up LVEF <35% (3.2% versus 7.4%; adjusted OR: 0.383; 95% CI: 0.051-2.884; P = .352) and LV remodeling (defined as >20% increase in LV end-diastolic volume; 37.1% versus 18.5%; adjusted OR: 2.249; 95% CI: 0.593-8.535; P = .234) were similar between groups.These data suggest that prolonged postprocedural anticoagulation may not provide much benefit after successful primary PCI in patients with STEMI. However, further studies are needed.


Assuntos
Anticoagulantes/uso terapêutico , Intervenção Coronária Percutânea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Remodelação Ventricular/efeitos dos fármacos
3.
Biomed Pharmacother ; 114: 108660, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974387

RESUMO

Dendritic cells (DCs) play a complex role in the progression of myocardial infarction (MI). The impact of angiotensin-converting enzyme (ACE) inhibitor therapy, partly via affecting DCs maturation and recruitment, was tested on a MI mouse model. Furthermore, the cardioprotective effects of ACEI were enhanced through attenuating migration of DCs from the spleen into peripheral circulation, thereby inhibiting DCs maturation and tissue inflammation. ACEI repress DCs immune inflammatory response through down-regulating DCs maturation surface markers and regulating inflammatory cytokines, which led to a higher survival rate, improved function and remodeling through decreased inflammatory response after MI. However, inhibition of AT2R activation, resulted in a reduction of ACEI effects on DCs. The potent anti-inflammatory effect of ACEI can partially be attributed to its impact on DCs through activation of AT2R, which may provide a new target mechanism for ACEI therapy after MI.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Dendríticas/efeitos dos fármacos , Coração/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Receptor Tipo 2 de Angiotensina/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Taxa de Sobrevida
4.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010001

RESUMO

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Masculino , Miocárdio/patologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
5.
Int J Mol Sci ; 20(4)2019 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-30813472

RESUMO

The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague⁻Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-α were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-α in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-α levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease.


Assuntos
Frutas/química , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo , Panax/química , Fenóis/uso terapêutico , Remodelação Ventricular , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Peso Corporal/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Citocinas/biossíntese , Diástole , Testes de Função Cardíaca , Imunofenotipagem , Inflamação/patologia , Masculino , Infarto do Miocárdio/patologia , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Fenóis/farmacologia , Ratos Sprague-Dawley , Remodelação Ventricular/efeitos dos fármacos
6.
Medicine (Baltimore) ; 98(12): e14907, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30896643

RESUMO

Evidence has shown that angiotensin II type 1 receptor antagonists have lower blood pressure and have target organ protective effects, but this is not the case for the drug allisartan isoproxil. The aim of this study was to evaluate the effects of allisartan isoproxil on blood pressure and target organ injury in patients with mild to moderate essential hypertension.In total, 80 essential hypertensive participants were randomly divided into an allisartan group and a nifedipine group (n = 40 per group), and their blood pressure was measured once per month for 6 months. A 2-dimensional echocardiogram was performed at baseline and at the end of the study. The serum levels of renal injury indexes, endothelial function markers, inflammatory factors, blood biochemical assays and urinary measurements were determined at baseline and at 6 months.At the end of the study, both systolic and diastolic blood pressure were significantly decreased in the allisartan group compared with baseline and showed the same antihypertensive effect as the nifedipine group. Meanwhile, the left ventricular remodeling, 24-hours levels of urinary microalbumin, endothelial dysfunction, and arterial stiffness were all significantly improved compared with that of the baseline and the nifedipine group (all P < .05).The present study showed that allisartan isoproxil had favorable blood pressure lowering and heart, renal, and endothelial protective effects in patients with mild to moderate essential hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Essencial/tratamento farmacológico , Imidazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Testes Hematológicos , Humanos , Imidazóis/efeitos adversos , Mediadores da Inflamação/metabolismo , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Nifedipino/uso terapêutico , Índice de Gravidade de Doença , Urinálise , Rigidez Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
7.
BMC Pharmacol Toxicol ; 20(1): 16, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841920

RESUMO

BACKGROUND: The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure. METHODS: Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles. RESULTS: In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p < 0.05) and an increased incidence of Early afterdepolarisations (+ 150%), while treatment with Entinostat in failing hearts could partially prevent this effect (from 250 ± 41 ms to 170 ± 53 ms, p < 0.05; reduction in EAD by 50%). Entinostat treatment partially restored KCNH2 and Cav1.3 gene expressions in failing hearts, and inhibited the development of cardiac fibrosis in vivo. CONCLUSION: In a rabbit model of heart failure, Entinostat diminishes heart failure related prolongation of repolarization and partially restores KCNH2 and Cav1.3 expression. In addition, Entinostat exerts antifibrotic properties both in vitro and in vivo. Thus, Entinostat might be an interesting candidate for the pharmaceutical therapy of heart failure directed against structural and electrical remodeling.


Assuntos
Benzamidas/farmacologia , Insuficiência Cardíaca/patologia , Inibidores de Histona Desacetilases/farmacologia , Piridinas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Potenciais de Ação , Animais , Canais de Cálcio Tipo L/fisiologia , Canal de Potássio ERG1/fisiologia , Feminino , Fibrose , Coração/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Miocárdio/patologia , Coelhos
8.
Planta Med ; 85(9-10): 708-718, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30822814

RESUMO

Right ventricle (RV) remodeling is a major pathological feature in pulmonary arterial hypertension (PAH). Magnesium lithospermate B (MLB) is a compound isolated from the roots of Salvia miltiorrhiza and it possesses multiple pharmacological activities such as anti-inflammation and antioxidation. This study aims to investigate whether MLB is able to prevent RV remodeling in PAH and the underlying mechanisms. In vivo, SD rats were exposed to 10% O2 for 21 d to induce RV remodeling, which showed hypertrophic features (increases in the ratio of RV weight to tibia length, cellular size, and hypertrophic marker expression), accompanied by upregulation in expression of NADPH oxidases (NOX2 and NOX4) and vascular peroxidase 1 (VPO1), increases in hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) production and elevation in phosphorylation levels of ERK; these changes were attenuated by treating rats with MLB. In vitro, the cultured H9c2 cells were exposed to 3% O2 for 24 h to induce hypertrophy, which showed hypertrophic features (increases in cellular size and hypertrophic marker expression). Administration of MLB or VAS2870 (a positive control for NOX inhibitor) could prevent cardiomyocyte hypertrophy concomitant with decreases in NOX (NOX2 and NOX4) and VPO1 expression, H2O2 and HOCl production, and ERK phosphorylation. Based on these observations, we conclude that MLB is able to prevent RV remodeling in hypoxic PAH rats through a mechanism involving a suppression of NOX/VPO1 pathway as well as ERK signaling pathway. MLB may possess the potential clinical value for PAH therapy.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hemeproteínas/metabolismo , Hipertensão Pulmonar/fisiopatologia , NADPH Oxidases/metabolismo , Peroxidases/metabolismo , Salvia miltiorrhiza/química , Remodelação Ventricular/efeitos dos fármacos , Animais , Fator Natriurético Atrial/genética , Benzoxazóis/farmacologia , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Hemeproteínas/antagonistas & inibidores , Hipertensão Pulmonar/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , NADPH Oxidases/antagonistas & inibidores , Peptídeo Natriurético Encefálico/genética , Peroxidases/antagonistas & inibidores , Ratos Sprague-Dawley , Triazóis/farmacologia
9.
Biomed Pharmacother ; 114: 108804, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30909146

RESUMO

B lymphocytes have been shown to contribute to autoimmune diseases via producing antibodies and proinflammatory cytokines. Depletion of B cells by blocking CD20 can inhibit these diseases. Here we examined whether an antibody against CD20, rituximab (RTX) (Rituxan@), used clinically in oncology could have similar anti-inflammatory effects in cardiac remodeling and heart failure (HF) in mice. Cardiac remodeling was established by pressure overload induced by transverse aortic constriction (TAC). Wild-type (WT) male C57BL/6 J mice were subjected to pressure overload by using transverse aortic constriction and then received RTX for 4 weeks. Administration of RTX markedly improves in vivo heart function, and suppressed heart chamber dilation, myocyte hypertrophy, fibrosis and oxidative stress in mice after TAC operation. RTX treatment also reversed established hypertrophic remodeling induced by TAC. Moreover, TAC-induced activation of multiple signaling pathways including calcineurin A, ERK1/2, STAT3, TGFß/Smad2/3 and IKKα/ß/NF-kB were remarkably attenuated in RTX-treated hearts compared with controls. These inhibitory effects of RTX were associated with inhibition of proinflammatory cytokine expression and Th2 cytokine-mediated IgG production from B cells. In conclusion, this study identifies that administration of RTX can inhibit pressure overload-induced cardiac remodeling and dysfunction in mice, and suggest that RTX may be a promising drug for treating hypertrophic disease.


Assuntos
Linfócitos B/efeitos dos fármacos , Coração/efeitos dos fármacos , Rituximab/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Hipertrofia/tratamento farmacológico , Hipertrofia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Int J Nanomedicine ; 14: 851-863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774338

RESUMO

Purpose: This study was carried out to investigate the effects of a triptolide (TP) nanosuspension and methotrexate (MTX) nanosuspension on left ventricular remodeling and cardiac function for autoimmune myocarditis (EAM) in rats. The regulating effects on inflammatory cytokines in the peripheral serum and related mechanisms are also discussed. Methods: First, TP and MTX were prepared as a nanosuspension, and the EAM model was successfully established in rats with cardiac myosin. Then, the effect of TP and MTX suspensions was tested in an EAM model. Results: Results revealed that both TP and MTX suspensions could reduce the degree of myocardial fibrosis and delay the remodeling process of the left ventricle which could further improve cardiac function. Finally, it was found that inflammatory cytokines in the peripheral serum were regulated by the nonspecific immune system and the inhibition of nuclear factor-κB signaling might have partly occurred due to this mechanism. Conclusion: In summary, this study provided a complete foundation for EAM therapy of profound clinical relevance.


Assuntos
Diterpenos/uso terapêutico , Metotrexato/uso terapêutico , Miocardite/tratamento farmacológico , Miocardite/fisiopatologia , Nanopartículas/química , Fenantrenos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/sangue , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Testes de Função Cardíaca , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Masculino , Metotrexato/farmacologia , Miocardite/sangue , Miocardite/diagnóstico por imagem , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Tamanho da Partícula , Fenantrenos/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Endogâmicos Lew , Transdução de Sinais/efeitos dos fármacos , Suspensões
11.
Int Heart J ; 60(2): 255-263, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30799375

RESUMO

Previous clinical studies have shown inconsistent results regarding the effect of erythropoietin in ST-segment elevation myocardial infarction (STEMI). This study investigated whether directed intracoronary infusion of darbepoetin-α into ischemic myocardium before reperfusion would reduce infarct size or post-infarct remodeling in STEMI patients.Eighty STEMI patients received one of the following treatments simultaneously with the first balloon inflation: intracoronary darbepoetin-α 300 µg (n = 40) or saline (n = 40), administered via the over-the-wire balloon system. The primary endpoint was infarct size estimated by serial cardiac enzyme levels after procedure. The secondary endpoints were (1) infarct size and proportion of salvaged myocardium measured with cardiac magnetic resonance (CMR) at baseline; (2) post-infarct remodeling (PIR), defined as an increase in left ventricular end-diastolic volume more than 20% at 4 months compared to the baseline on CMR; and (3) composite cardiovascular endpoints assessed at 4 months.The peak CK-MB [median 270.0 (interquartile range 139.8-356.3) versus 231.5 (131.0-408.5) ng/mL, P = 0.55] and troponin-I [128.5 (63.5-227.8) versus 109.0 (43.8-220.0) ng/mL, P = 0.52) ] did not differ between the darbepoetin-α and control group. Fifty-seven patients completed the baseline and 4-month follow-up CMR. There were no differences in infarct size [30.6 (18.1-49.8) versus 31.5 (22.5-47.3) cm3, P = 0.91), proportion of salvaged myocardium [26.7% (15.9-42.6%) versus 35.8% (22.4-48.8%), P = 0.12) or PIR (8.0% versus 6.7%, P = 0.62) between the two groups. Composite cardiovascular outcomes did not differ between the two groups.In conclusion, administration of intracoronary darbepoetin-α before reperfusion did not reduce infarct size or post-infarct remodeling in STEMI patients.


Assuntos
Angioplastia Coronária com Balão/métodos , Darbepoetina alfa , Miocárdio/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Remodelação Ventricular/efeitos dos fármacos , Idoso , Vasos Coronários , Darbepoetina alfa/administração & dosagem , Darbepoetina alfa/efeitos adversos , Monitoramento de Medicamentos/métodos , Feminino , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Humanos , Infusões Intra-Arteriais , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
12.
Int Heart J ; 60(2): 411-418, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30745531

RESUMO

The effect of DPP-4 inhibitor on the electrical and structural remodeling in myocardial injury has not been evaluated. We hypothesized that linagliptin, DPP-4 inhibitor, suppresses myocardial remodeling in the isoproterenol (ISP)-induced myocardial injury model.Sprague-Dawley rats were assigned to 3 groups: 1) sham group, 2) ISP group (subcutaneous ISP injection of 70 mg/kg), and 3) ISP + linagliptin (ISP + Lin) (5 mg/kg/day, p.o.) group. Serum was sampled on day 1 (acute phase) and day 7 (sub-acute phase) to evaluate derivatives of reactive oxidative metabolites (d-ROMs). The electrophysiological study was performed in sub-acute phase for the evaluation of the ventricular effective refractory period (VERP) and monophasic action potential duration (MAPD). The VERP and MAPD were markedly prolonged in the ISP group in comparison with the sham (MAPD20: 14 ± 6 versus 11 ± 3 ms, MAPD90: 57 ± 8 versus 44 ± 7 ms, VERP: 74 ± 22 versus 38 ± 10 ms, P < 0.05). In contrast in the ISP + Lin group, such prolongations were suppressed, and the parameters were shorter than the ISP group (MAPD20: 9 ± 2 ms, MAPD90: 35 ± 6 ms, VERP: 52 ± 13 ms, P < 0.05). ISP treatment induced myocardial injury. The injured area was reduced in the ISP + Lin group in comparison with the ISP group (P < 0.05). Serum d-ROMs level in acute phase was higher in ISP group than the other 2 groups (sham: 214 ± 55 versus ISP: 404 ± 45 versus ISP + Lin: 337 ± 20 U.CARR, P < 0.05).Linagliptin suppressed structural and electrical changes, possibly through the antioxidative effect, in this myocardial injury model.


Assuntos
Remodelamento Atrial/efeitos dos fármacos , Linagliptina/farmacologia , Infarto do Miocárdio , Remodelação Ventricular/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Técnicas Eletrofisiológicas Cardíacas/métodos , Isoproterenol/farmacologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
13.
Cardiovasc Diabetol ; 18(1): 15, 2019 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-30710997

RESUMO

BACKGROUND: Hyperglycaemia associated with myocardial oxidative stress and fibrosis is the main cause of diabetic cardiomyopathy. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor has recently been reported to improve glycaemic control in patients with type 2 diabetes in an insulin-independent manner. The aim of this study was to investigate the effect of empagliflozin on myocardium injury and the potential mechanism in type 2 diabetic KK-Ay mice. METHODS: Thirty diabetic KK-Ay mice were administered empagliflozin (10 mg/kg/day) by oral gavage daily for 8 weeks. After 8 weeks, heart structure and function were evaluated by echocardiography. Oxidants and antioxidants were measured and cardiac fibrosis was analysed using immunohistochemistry, Masson's trichrome stain and Western blot. RESULTS: Results showed that empagliflozin improved diabetic myocardial structure and function, decreased myocardial oxidative stress and ameliorated myocardial fibrosis. Further study indicated that empagliflozin suppressed oxidative stress and fibrosis through inhibition of the transforming growth factor ß/Smad pathway and activation of Nrf2/ARE signaling. CONCLUSIONS: Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice. Taken together, these results indicate that the empagliflozin is a promising agent for the prevention and treatment of diabetic cardiomyopathy.


Assuntos
Antioxidantes/farmacologia , Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Glucosídeos/farmacologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Elementos de Resposta Antioxidante , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Fibrose , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
Phytomedicine ; 57: 255-261, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30797987

RESUMO

BACKGROUND: Following myocardial infarction (MI), a series of structural and functional changes evolves in the myocardium, collectively defined as cardiac remodeling. PURPOSE: The aim of present study was to investigate the cardioprotection of salvianolicacid B (SalB) and ginsenoside Rg1 (Rg1) combination against cardiac remodeling in a rat model at the subacute phase of MI and further elucidate the underlying mechanism. METHODS: Rat heart was exposed via a left thoracotomy at the fourth intercostal space and MI was induced by a ligature below the left descending coronary artery. Hemodynamic assay was conducted using a Mikro-tipped SPR-320 catheter which was inserted through the right carotid artery into left ventricle.Myocardial infarct size was detected using 3,5-triphenyltetrazolium chloride (TTC) staining. Haematoxylin and eosin (HE) stain and picric sirius red stain were conducted for histopathological detection. Immunohistochemistry was used to detect the expression of α-smooth muscle actin (α-SMA) and gelatin zymography was used to evaluate the activities of matrix metalloproteinase-9 (MMP-9). RESULTS: Comparing with MI rats, 30 mg/kg SalB-Rg1 improved cardiac function verified by maximum rate of pressure development for contraction (+dp/dtmax, p < 0.01) and maximum rate of pressure development for relaxation (-dp/dtmax, p < 0.05); reduced myocardial infarct size (p < 0.05) verified by TTC staining, improved cardiac structure based on HE stain; decreased collagen volume fraction (p < 0.05) and collagen I/III ratio (p < 0.05) according picrosirius red staining. The underlying mechanism of SalB-Rg1 against cardiac remodeling was associated with its down-regulation on α-SMA expression according immunohistochemistry (p < 0.01) and inhibition on MMP-9 activity based on in-gel zymography (p < 0.05). CONCLUSION: All above study indicated the potential therapeutic effects of SalB-Rg1 on heart.


Assuntos
Benzofuranos/farmacologia , Cardiotônicos/farmacologia , Ginsenosídeos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Colágeno/metabolismo , Quimioterapia Combinada , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Ratos Wistar , Remodelação Ventricular/efeitos dos fármacos
15.
Int J Cardiovasc Imaging ; 35(7): 1309-1318, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30790116

RESUMO

Hypertrophic cardiomyopathy (HCM) is associated with increased left ventricular (LV) mass, decreased myocardial strain, and the presence of LV fibrosis and scar. The relationship between LV scar and fibrosis with left atrial (LA) fibrosis in the setting of HCM has not been examined. The purpose of this study is to demonstrate a correlation between the degree of LA fibrosis and LV parameters in subjects with HCM. Twenty-eight subjects with HCM were imaged on a 1.5T MRI scanner with cine, LV and LA late gadolinium enhancement (LGE) sequences. LA LGE and LA measurements were correlated with LV measurements of volumes, mass, strain, and LGE. Other clinical conditions and medication usage were also examined and evaluated for correlation with LA and LV parameters. LV LGE was identified in 24 (86%) of the cases and LA LGE was identified in all of the cases. Extent of LA fibrosis significantly correlated with percent LV LGE (r = 0.64, p = 0.001), but not with indexed LV mass or maximum wall thickness. Extent of LA fibrosis also moderately correlated with decreased LV global strain (radial, r = - 0.50, p = 0.013; circumferential, r = 0.47, p = 0.02; longitudinal, r = 0.52, p = 0.013). Increased LA systolic volume correlated moderately with LV end diastolic volume (r = 0.50, p = 0.006). Patients on therapy with Renin-Angiotensin-Aldosterone System (RAAS) Inhibition had significantly less LA LGE compared to those without (18.6% vs 10.8%, p = 0.023). LA fibrosis, as measured by LGE, is prevalent in HCM and is correlated with LV LGE. The correlation between LA and LV LGE might suggest either that LA fibrosis is a consequence of LV remodeling, or that LA and LV fibrosis are both manifestations of the same cardiomyopathic process. Further study is warranted to determine the causality of LA scar in this population.


Assuntos
Função do Átrio Esquerdo , Remodelamento Atrial , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Átrios do Coração/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Remodelação Ventricular , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Função do Átrio Esquerdo/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Meios de Contraste/administração & dosagem , Feminino , Fibrose , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Compostos Organometálicos/administração & dosagem , Valor Preditivo dos Testes , Estudos Retrospectivos , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
16.
Eur J Pharmacol ; 847: 61-71, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684466

RESUMO

Following myocardial infarction, the heart undergoes a series of dramatic compensations which may later form a maladaptive picture characterized by ventricular dilation and pump failure. Among several opioid agents, morphine has been shown to confer protection against reperfusion injury and infarct size. Here, we sought to study the cardioprotective effect of post-infarct morphine treatment against left ventricular adverse remodeling. We induced myocardial infarction in male Sprague - Dawley rats by ligating left anterior descending artery and then, treated these animals with three different doses of morphine -0.3, 3 and 10 mg/kg (i.p.). The echocardiographic evaluation depicted improved cardiac performance and lesser chamber dilation in the animals that had received 3 mg/kg of morphine. Next, we studied the effect of 3 mg/kg morphine administration on left ventricular hemodynamics, infarct size, tissue architecture, changes in lung and heart weight, circulating TNF-α level and post-MI mRNA expression of collagen-1, collagen-3, TGF-ß, TNF-α, MMP-2 and MMP-9. Five-day morphine administration markedly improved LV function, and also reduced infarct size, myocyte hypertrophy, fibrosis, index of infarct expansion, heart weight and serum TNF-α level. Moreover, morphine alleviated MI-induced increase in wet and dry lung weight. Morphine also altered the mRNA expression of fibrosis-related genes, TNF-α, MMP-2 and MMP-9. In conclusion, post-infarct morphine treatment can mitigate adverse remodeling and cardiac dysfunction after MI. Beside analgesic effect, we may be able to harvest benefits from the antifibrotic and anti-remodeling action of morphine in patients with the acute coronary syndrome.


Assuntos
Ventrículos do Coração/efeitos dos fármacos , Morfina/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Ecocardiografia/métodos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Ventrículos do Coração/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Reperfusão/métodos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Disfunção Ventricular Esquerda/metabolismo
17.
Biomed Pharmacother ; 111: 695-704, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611994

RESUMO

Paeoniflorin (PF) is a main bioactive component of the root of Paeonia lactiflora Pal, and previous investigations suggest that it may impact cardiac remodeling in spontaneous hypertensive rats (SHR) via the MAPK signaling pathway. Thus, the purpose of this investigation was to examine the impacts of paeoniflorin cardiac function in SHR rats. Cardiac function and blood pressure were observed using echocardiography and non-invasive tail pressure gauge. Heart histopathology was assessed by histological staining and transmission electron microscopy. Genomic sequencing was performed and signaling pathway enrichment analyzed the function of differentially expressed genes(DEGs). Biochemical kits were used to analyze the serum level of proinflammatory cytokines including TNF-α, IL-6 and MCP-1. qRT-PCR proved the mRNA expression of Ngfr, Grin2b, and Ntf4. MAPK pathways were determined via western blot. Paeoniflorin decreased blood pressure and increased hemodynamic indexes. 131 DEGs were identified (SHR vs. PF), and mainly enriched on the MAPK signaling pathway. Paeoniflorin reduced IL-6, MCP-1, Ngfr, Grin2b, and Ntf4, and also decreased p-JNK, p-Erk1/2, and p-p38 proteins compared with the SHR group. Paeoniflorin attenuated cardiac hypertrophy, cardiac fibrosis, and inflammation, and subsequently improved LV function. In conclusion, the cardioprotective role of paeoniflorin was associated with the inhibition of MAPK signaling pathway.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Glucosídeos/uso terapêutico , Hipertensão/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monoterpenos/uso terapêutico , Paeonia , Remodelação Ventricular/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/fisiologia , Glucosídeos/farmacologia , Hipertensão/enzimologia , Hipertensão/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Monoterpenos/farmacologia , Ratos , Ratos Endogâmicos SHR , Remodelação Ventricular/fisiologia
18.
Phytomedicine ; 56: 83-93, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668357

RESUMO

BACKGROUND: Cardiac atrophy and reduced cardiac distensibility have been reported following space flight. Cardiac function is correspondingly regulated in response to changes in loading conditions. Panax quinquefolium saponin (PQS) improves ventricular remodeling after acute myocardial infarction by alleviating endoplasmic reticulum stress and Ca2+overload. However, whether PQS can ameliorate cardiac atrophy following exposure to simulated microgravity remains unknown. PURPOSE: To explore the protective role of PQS in cardiac remodeling under unloading conditions and its underlying mechanisms. METHODS: Hindlimb unloading (HU) model was used to simulate unloading induced cardiac remodeling. Forty-eight male rats were randomly assigned to four groups, including control, PQS, HU and HU + PQS. At 8 weeks after the experiment, cardiac structure and function, serum levels of Creatine Kinase-MB (CK-MB), Cardiactroponin T (cTnT), ischemia modified albumin (IMA), and cardiomyocyte apoptosis were measured. Network pharmacology analysis was used to predict the targets of the six major constituents of PQS, and the signaling pathways they involved in were analyzed by bioinformatics methods. Changes in the key proteins involved in the protective effects of PQS were further confirmed by Western Blot. RESULTS: Simulated microgravity led to increases in serum levels of CK-MB, cTnT and IMA, remodeling of cardiac structure, impairment of cardiac function, and increased cardiomyocyte apoptosis as compared with control. PQS treatment significantly reduced serum levels of CK-MB, cTnT and IMA, improved the impaired cardiac structure and function, and decreased cardiomyocyte apoptosis induced by unloading. The activation of AMPK and inhibition of Erk1/2 and CaMKII/HDAC4 were demonstrated in the cardiocytes of HU rats after PQS treatment. CONCLUSION: PQS provides protection against cardiac remodeling induced by simulated microgravity, partly resulting from changes in the signaling pathways related to energy metabolism reduction, calcium overloading and cell apoptosis.


Assuntos
Cardiotônicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Saponinas/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Ausência de Peso/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Infarto do Miocárdio/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Albumina Sérica/análise , Albumina Sérica Humana , Transdução de Sinais/efeitos dos fármacos
19.
Basic Res Cardiol ; 114(2): 11, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30673858

RESUMO

Coxsackieviruses of group B (CVB) are well-known causes of acute and chronic myocarditis. Chronic myocarditis can evolve into dilated cardiomyopathy (DCM) characterized by fibrosis and cardiac remodeling. Interleukin-1ß (IL-1ß) plays a decisive role in the induction of the inflammatory response as a consequence of viral replication. In this study, we analyzed the effects of IL-1ß neutralization on the transition of acute to chronic myocarditis in a mouse model of CVB3 myocarditis. Mice were treated with an anti-murine IL-1ß antibody as a surrogate for Canakinumab at different time points post CVB3 infection. Treatment was performed in the early phase (day 1-14 pi, day 3-14 pi) or at a later stage of myocarditis (day 14-28 pi). Subsequently, the hearts were examined histologically, immunohistochemically and by molecular biology. A significant reduction of viral replication, cardiac damage and inflammation was found after administration of the antibody in the early phase and in the later phase of infection. Furthermore, less collagen I deposition and a considerable reduction of fibrosis were found in antibody-treated mice. Using microarray analysis, a significant upregulation of various extracellular matrix and fibrosis-associated molecules was found in CVB3-infected mice, including TGF-ß, TIMP-1 and MMP12, as well as diverse matricellular proteins, whereas, these molecules were significantly downregulated in all IL-1ß antibody-treated infected mice. Neutralization of IL-1ß at different stages of enteroviral infection prevents the development of chronic viral myocarditis by reducing inflammation, interstitial fibrosis and adverse cardiac remodeling. These findings are relevant for the treatment of patients with acute and chronic myocarditis.


Assuntos
Interleucina-1beta/antagonistas & inibidores , Miocardite/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Doença Crônica , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/patologia , Enterovirus Humano B , Camundongos , Miocardite/metabolismo , Miocardite/virologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
20.
Cardiovasc Diabetol ; 18(1): 1, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626440

RESUMO

BACKGROUND: In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). METHODS: Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg-1 week-1 starting at 1 week post-MI) for 3 weeks. RESULTS: Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0 ± 2.3% vs 30.7 ± 1.7% in vehicle-treated MI heart, p < 0.05) and limited adverse remodelling (LV mass: 129 ± 7 vs 176 ± 14 mg in vehicle-treated MI hearts, p < 0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661 ± 192 vs 924 ± 165 nmol g dry wt-1 min-1 in vehicle-treated MI hearts, p < 0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3ß pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374 ± 27 vs 183 ± 41 µmol g protein-1 in vehicle-treated MI hearts, p < 0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor ß-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment. CONCLUSIONS: mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.


Assuntos
Anticorpos Monoclonais/farmacologia , Resistência à Insulina , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Receptores de Glucagon/antagonistas & inibidores , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Preparação de Coração Isolado , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Receptores de Glucagon/metabolismo , Recuperação de Função Fisiológica , Transdução de Sinais/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
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