RESUMO
Prevention of left ventricular remodeling is an important therapeutic target post-myocardial infarction. Experimentally, treatment with growth hormone (GH) is beneficial, but sustained local administration has not been thoroughly investigated. We studied 58 rats (322 ± 4 g). GH was administered via a biomaterial-scaffold, following in vitro and in vivo evaluation of degradation and drug-release curves. Treatment consisted of intra-myocardial injection of saline or alginate-hydrogel, with or without GH, 10 min after permanent coronary artery ligation. Echocardiographic and histologic remodeling-indices were examined 3 weeks post-ligation, followed by immunohistochemical evaluation of angiogenesis, collagen, macrophages and myofibroblasts. GH-release completed at 3 days and alginate-degradation at â¼7 days. Alginate + GH consistently improved left ventricular end-diastolic and end-systolic diameters, ventricular sphericity, wall tension index and infarct-thickness. Microvascular-density and myofibroblast-count in the infarct and peri-infarct areas were higher after alginate + GH. Macrophage-count and collagen-content did not differ between groups. Early, sustained GH-administration enhances angiogenesis and myofibroblast-activation and ameliorates post-infarction remodeling.
Assuntos
Hormônio do Crescimento/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Remodelação Ventricular , Alginatos/química , Animais , Ácido Glucurônico/química , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/farmacologia , Ácidos Hexurônicos/química , Hidrogéis/química , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Wistar , Alicerces Teciduais/químicaRESUMO
Thyroid hormone receptor α1 (TRα1) is shown to be critical for the maturation of cardiomyocytes and for the cellular response to stress. TRα1 is altered during post ischemic cardiac remodeling but the physiological significance of this response is not fully understood. Thus, the present study explored the potential consequences of selective pharmacological inhibition of TRα1 on the mechanical performance of the post-infarcted heart. Acute myocardial infarction was induced in mice (AMI), while sham operated animals served as controls (SHAM). A group of mice was treated with debutyl-dronedarone (DBD), a selective TRα1 inhibitor (AMI-DBD). AMI resulted in low T3 levels in plasma and in down-regulation of TRα1 and TRß1 expression. Left ventricular ejection fraction (LVEF%) was significantly reduced in AMI [33 (SEM 2.1) vs 79(2.5) in SHAM, p < 0.05] and was further declined in AMI-DBD [22(1.1) vs 33(2.1), respectively, p < 0.05]. Cardiac mass was increased in AMI but not in AMI-DBD hearts, resulting in significant increase in wall tension index. This increase in wall stress was accompanied by marked activation of p38 MAPK, a kinase that is sensitive to mechanical stretch and exerts negative inotropic effect. Furthermore, AMI resulted in ß-myosin heavy chain overexpression and reduction in the ratio of SR(Ca)ATPase to phospholamban (PLB). The latter further declined in AMI-DBD mainly due to increased expression of PLB. AMI induces downregulation of thyroid hormone signaling and pharmacological inhibition of TRα1 further depresses post-ischemic cardiac function. p38 MAPK and PLB may, at least in part, be involved in this response.
Assuntos
Amiodarona/análogos & derivados , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Receptores alfa dos Hormônios Tireóideos/metabolismo , Amiodarona/farmacologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Dronedarona/análogos & derivados , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/sangue , Infarto do Miocárdio/tratamento farmacológico , Isquemia Miocárdica/sangue , Isquemia Miocárdica/tratamento farmacológico , Miosinas/metabolismo , Tamanho do Órgão , Isoformas de Proteínas/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Transdução de Sinais , Volume Sistólico , Receptores alfa dos Hormônios Tireóideos/antagonistas & inibidores , Hormônios Tireóideos/sangue , Função Ventricular EsquerdaRESUMO
The present study explored the effects of thyroid hormone (TH) treatment on post-ischemic cardiac function and potential implicated mechanisms. Acute myocardial infarction (AMI) was induced in mice by coronary artery ligation while sham-operated animals served as controls. This procedure resulted in a marked depression of cardiac function and significant reduction in TH levels in plasma. TH was given at a dose aiming to normalize T3 levels in plasma [AMI-TH (A)] and also at higher doses. The group of animals treated with the highest dose of TH, which displayed significantly increased mortality rate was included in the study [AMI-TH (B)]. In AMI-TH (A) mice, TH significantly improved left ventricular (LV) ejection fraction (EF%), [27.9% (1.4) in AMI versus 38.0 (3.1) in AMI-TH (A), P < 0.05], and favorably remodeled LV chamber while α-MHC was the dominant isoform expressed. In AMI-TH (B) mice, TH treatment resulted in increased mortality as compared to untreated mice (73% vs 47%, P < 0.05), while the favorable effect of TH was not evident in the survived animals. At the molecular level, TH, at the replacement dose, modestly increased p-Akt levels in the myocardium without any change in p-ERK levels. On the contrary, TH at the higher dose resulted in further increase in p-Akt along with an increase in p-ERK levels. In conclusion, TH appears to have a dose-dependent bimodal effect on post-ischemic cardiac performance and this effect may, at least in part, be mediated by a distinct pattern of activation of Akt and ERK signaling.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Terapia de Reposição Hormonal , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiroxina/administração & dosagem , Tri-Iodotironina/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Cadeias Pesadas de Miosina/metabolismo , Fosforilação , Volume Sistólico/efeitos dos fármacos , Tiroxina/sangue , Tri-Iodotironina/sangue , Ultrassonografia , Remodelação Ventricular/efeitos dos fármacosRESUMO
Ranolazine (RAN) is known to exert both anti-ischemic and antidiabetic actions. Thus, this study has explored the hypothesis that RAN would have greater effect on the recovery of cardiac function in diabetic mellitus (DM) rat hearts following myocardial infarction (MI). Myocardial infarction was induced in nondiabetic (MI, n = 14) and diabetic (streptozotocin induced; DM-MI, n = 13) Wistar rats by permanent ligation of the left coronary artery. Cardiac function was evaluated using echocardiography (left ventricular ejection fraction %) and in isolated heart preparations by measuring left ventricular developed pressure (LVDP), and the positive and negative first derivative of LVDP (± dp/dt). Ranolazine (20 mg/kg, ip once a day) was administered 24 hours after surgical procedure for 4 weeks to nondiabetic (MI + RAN, n = 17) and diabetic rats (DM-MI + RAN, n = 15). The RAN improved the recovery of function in both the nondiabetic and the diabetic postinfarcted hearts but this effect was greater and achieved statistical significance only in the diabetic group. The RAN resulted in increased levels of phosphorylated protein kinase B (Akt) and mammalian target of rapamycin (mTOR, a component of Akt signaling) in both nondiabetic and diabetic infarcted hearts without changes in the activation of mitogen-activated protein kinases (MAPKs; p38 MAPK, c-Jun N-terminal kinase, and extracellular signal-regulated kinase). In addition, in diabetic hearts, RAN resulted in a significant increase in the ratio of sarcoplasmic Ca(2+)-ATPase/phospholamban (a target of Akt signaling, 2.0-fold increase) and increased levels of phosphorylated calcium-regulated adenosine monophosphate-activated protein kinase (AMPK; 2.0-fold increase). In diabetic animals, RAN increased insulin and lowered glucose levels in serum. In conclusion, the beneficial effect of RAN on the recovery of cardiac function after MI was greater in DM rats. This response was associated with activation of Akt/mTOR and AMPK. These findings provide a plausible explanation for the results of the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial, which showed a greater antianginal effect of RAN in patients with coronary artery disease and diabetes.
Assuntos
Acetanilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Piperazinas/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Ecocardiografia , Eletroforese em Gel de Poliacrilamida , Testes de Função Cardíaca , Insulina/sangue , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ranolazina , Ratos , Ratos Wistar , Resultado do Tratamento , Função Ventricular Esquerda , Proteínas Quinases p38 Ativadas por Mitógeno/sangueRESUMO
OBJECTIVE: Thyroid hormone (TH) is shown to be protective against cardiac and pancreatic injury. Thus, this study explored the potential effects of TH treatment on the functional status of the postinfarcted diabetic myocardium. Diabetic patients have worse prognosis after acute myocardial infarction (AMI). MATERIALS/METHODS: AMI was induced by left coronary ligation in rats previously treated with 35 mg/kg streptozotocin (STZ), (DM-AMI). TH treatment was initiated at 2 weeks after AMI and continued for 6 weeks (DM-AMI+TH), while sham-operated animals served as control (DM-SHAM). RESULTS: TH treatment increased cardiac mass, improved wall stress and favorably changed cardiac geometry. TH significantly increased echocardiographic left ventricular ejection fraction (LVEF%): [54.2 (6.5) for DM-AMI+TH vs 37 (2.0) for DM-AMI, p<0.05]. TH treatment resulted in significantly increased insulin and decreased glucose levels in serum. The ratios of phosphorylated (p)-Akt/total Akt and p-mTOR/total mTOR were increased 2.0 fold and 2.7 fold in DM-AMI+TH vs DM-AMI respectively, p<0.05. Furthermore, the ratio of p-AMPK/total AMPK was found to be increased 1.6 fold in DM-AMI+TH vs DM-AMI, p<0.05. CONCLUSION: TH treatment improved the mechanical performance of the post-infarcted myocardium in rats with STZ-induced diabetes, an effect which was associated with Akt/mTOR and AMPK activation.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Complicações do Diabetes/tratamento farmacológico , Coração/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Hormônios Tireóideos/farmacologia , Animais , Glicemia/metabolismo , Cardiomegalia/sangue , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Complicações do Diabetes/sangue , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Insulina/sangue , Insulina/metabolismo , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Regulação para CimaRESUMO
OBJECTIVES: The present study investigated the potential of the failing myocardium of patients with ventricular assist devices (VAD) to respond to physiological growth stimuli, such as exercise, by activating growth signalling pathways. This may be of therapeutic relevance in identifying novel pharmacological targets for therapies that could facilitate recovery after VAD implantation. METHODS: Twenty-two patients bridged to heart transplantation (HTx) with VAD were included in the study. A group of patients underwent moderate intensity aerobic exercise (GT), while another group of patients did not receive exercise training (CG). Thyroid hormone receptor alpha1 (TRα1) protein and total (t) and phosphorylated (p) protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) kinase signalling were measured in myocardial tissue by western blotting at pre-VAD and pre-HTx period. In addition, Thyroid hormone (TH) levels were measured in plasma. RESULTS: Peak oxygen consumption (VO2) at pre-HTx period was higher in patients subjected to training protocol [18.0 (0.8) for GT when compared with 13.7 (0.7) for CG group, P = 0.002]. N-terminal-prohormone of brain natriuretic peptide (NT-proBNP) levels were 1068 (148) for CG vs 626 (115) for GT group, P = 0.035. A switch towards up-regulation of physiological growth signalling was observed: the ratio of p-Akt/t-Akt was 2-fold higher in GT vs CG, P < 0.05 while p-JNK/t-JNK was 2.5-fold lower (P < 0.05) in GT vs CG, in pre-HTx samples. This response was accompanied by a 2.0-fold increase in TRα1 expression in pre-HTx samples with concomitant increase in circulating T3 in GT vs CG, P < 0.05. No differences in peak VO2, NT-proBNP, T3, TRα1, p/t-AKT and p/t-JNK were found between groups in the pre-VAD period. CONCLUSIONS: The unloaded failing myocardium responded to physical training by enhancing thyroid hormone signalling. This response was associated with an up-regulation of Akt and suppression of JNK activation.