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BACKGROUND: Small bowel bleeding is an uncommon cause of lower gastrointestinal bleeding, which may require different management. CASE PRESENTATION: A 37-year-old man presenting with hematochezia was promptly diagnosed with small bowel bleeding by computed tomography angiography. Transcatheter arterial embolization was carried out because the patient's hemodynamic status deteriorated. Hemostasis was achieved by embolization with imipenem/cilastatin, although superselective embolization failed. Capsule endoscopy revealed multiple ulcers and erosions. Drug-induced small bowel injury was suspected to be the cause of small bowel bleeding. CONCLUSION: Computed tomography angiography can facilitate the management of lower gastrointestinal bleeding. Considering transcatheter arterial embolization and choosing an optimal embolic agent depending on the situation are important in the management of hemodynamically unstable patients.
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Molnupiravir is a novel antiviral agent for coronavirus disease 2019 (COVID-19) treatment. Warfarin is an oral anticoagulation agent with difficult management due to drug interactions. Here, we describe a case of international normalized ratio (INR) prolongation in a patient who administrated warfarin with molnupiravir for COVID-19. An increased INR at 3.80, enough to discontinue warfarin, was observed on the fifth day of molnupiravir therapy, although the warfarin dose and INR were stable at 4 mg/day and approximately 2.0 before the molnupiravir initiation, respectively. Factors that affect the INR, such as severe COVID-19, cytokine, diet, liver dysfunction, and the concomitant use of medications other than molnupiravir, were unlikely in this patient. This case suggests that healthcare physicians should be aware of the possibility of drug interaction between molnupiravir and warfarin.
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BACKGROUND: Chronic total occlusion (CTO) in a non-infarct-related artery (IRA) in patients with acute coronary syndrome (ACS) is associated with a poor prognosis. However, whether the prognostic impact of non-IRA CTO differs according to left ventricular ejection fraction (LVEF) is unclear. METHODS AND RESULTS: A total of 2060 consecutive acute myocardial infarction (AMI) patients who underwent primary percutaneous coronary intervention (PCI) were classified into 2 groups according to their LVEF (reduced EF: LVEF < 50%, preserved EF: LVEF ≥ 50%) and further subdivided according to the presence of concomitant non-IRA CTO. In the reduced EF group, patients with CTO had a higher 1-year all-cause death rate (20.3% vs. 34.3%, P = 0.001) and major adverse cardiac event rate (MACE: 19.6% vs. 39.6%, P < 0.001) compared to those without CTO, but they were similar between patients with and without CTO in the preserved EF group. Non-IRA CTO was an independent predictor of all-cause death (HR 1.58, 95% CI 1.06-2.33, P = 0.02) and MACE (HR 1.67, 95% CI 1.14-2.46, P = 0.009) only in the reduced EF group. In addition, the outcomes of successful CTO-PCI seemed to be similar to those without CTO in the reduced EF group. CONCLUSIONS: CTO in a non-IRA may contribute to a poor prognosis only in AMI patients with reduced LVEF.
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INTRODUCTION:: Aortic mural thrombosis associated with a malignant disease is rare, and whether anticoagulation therapy or surgical treatment is the more definitive primary treatment remains uncertain. This study aims to determine the best treatment strategy for aortic thrombosis in a patient with a malignant disease. METHODS:: We reviewed medical literature using the PubMed database and present a case of aortic thrombosis due to a hypercoagulable state related to sigmoid colon adenocarcinoma. RESULTS:: Of the 18 patients from 14 articles included in this study, 13 received simple anticoagulation as a primary treatment (anticoagulation group), while 5 underwent surgical treatment (surgical treatment group). Recurrence or exacerbation of embolism was found in 2 (15.4%) of the 13 patients and in 1 (20.0%) of the 5 patients ( P = 1.0). Major complications were observed in 1 (7.7%) of the patients in the anticoagulation group and in 1 (20.0%) of the 5 patients in the surgical treatment group ( P = .49). No significant differences between the groups were found. CONCLUSIONS:: A simple anticoagulation therapy may be as effective as surgical treatment in patients with aortic thrombosis associated with malignancy.
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Adenocarcinoma/complicações , Doenças da Aorta/etiologia , Neoplasias do Colo Sigmoide/complicações , Trombose/etiologia , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Anticoagulantes/administração & dosagem , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/tratamento farmacológico , Aortografia/métodos , Angiografia por Tomografia Computadorizada , Feminino , Fibrinolíticos/administração & dosagem , Heparina/administração & dosagem , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo Sigmoide/sangue , Neoplasias do Colo Sigmoide/diagnóstico , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Resultado do TratamentoRESUMO
INTRODUCTION: Reduction en masse is a rare complication of inguinal hernia. This condition is defined as the displacement of a strangulated hernia mass into the preperitoneal space. CASE PRESENTATION: A 62-year-old man presented with severe abdominal pain after a forcible reduction of an incarcerated right inguinal hernia. Abdominal computed tomography (CT) scan suggested strangulated bowel. Emergency exploratory laparoscopy was performed and the incarcerated bowel was successfully released. Elective preperitoneal inguinal hernia repair using the Modified Kugel™ Patch was performed under laparoscopic guidance. The patient made an uneventful recovery. DISCUSSION: Reduction en masse should be considered when abdominal pain persists after a difficult reduction of inguinal hernia. Laparoscopic guidance led to the definitive repair of the inguinal hernia with reduction en masse. CONCLUSION: Laparoscopic relief can be an efficient therapeutic option for the management of this condition. In addition, Modified Kugel™ Patch repair with ligation of the hernia sac could be a reasonable treatment.
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INTRODUCTION: Nonocclusive mesenteric ischemia (NOMI) has been reported to be associated with high mortality. Early diagnosis of NOMI and prompt restoration of the intestinal blood flow is necessary in order to achieve a favorable outcome. PRESENTATION OF CASE: We present the case of a patient who developed NOMI after autologous blood collection and was treated by selective infusion of the superior mesenteric artery with papaverine, intestinal decompression using a long intestinal tube, the administration of antibiotics, and fluid replacement. Although this non-surgical management was successful, 8 weeks after the ischemic event, segmental bowel resection was necessary because of repeated intestinal obstruction caused by bowel stricture. DISCUSSION: Autologous blood collection might be a risk factor of NOMI. In addition, the possibility of delayed intestinal stenosis remains, even if bowel necrosis and surgical resection were avoided with non-surgical management including vasodilator therapy. CONCLUSION: Rapid diagnosis and intervention are essential to minimize intestinal ischemia.
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Anomalous origin of the left coronary artery from the pulmonary artery is rare but causes myocardial ischemia and sudden death. A few patients with this anomaly can survive to adulthood without sufficient collateral coronary flow or surgical intervention. We present here a case of acute inferior myocardial infarction, which may occur due to thrombotic occlusion of the right coronary artery, in a 63-year-old woman with anomalous origin of the left coronary artery from the pulmonary artery, providing specific coronary angiographic findings.
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Long-acting Ca(2+)-channel blockers have been reported to be effective in treating ischemic heart disease. However, their effects on cardiac remodeling after myocardial infarction (MI) are still unclear. We performed this study to examine the effect of azelnidipine on left ventricular (LV) remodeling, including systolic and diastolic dysfunction, in rats with MI. MI was induced by ligation of the left anterior descending artery. The rats were then separated into 3 groups: a sham-operated group (n = 9), untreated MI group (n = 10), and azelnidipine-treated MI group (n = 10). Four weeks after MI, hemodynamic measurements and Doppler echocardiographic assessment were performed. LV weight and LV end-diastolic dimension were significantly higher in the untreated MI group than in the sham-operated group. Azelnidipine significantly prevented the increases in these parameters. Azelnidipine also improved the ejection fraction (42 +/- 3%, P<0.05) and the E wave to A wave ratio (3.2 +/- 0.5, P<0.05), compared with the untreated MI group (31 +/- 3% and 5.3 +/- 0.8, respectively). In conclusion, azelnidipine can prevent LV remodeling and improve systolic and diastolic function after MI. Administration of long-acting Ca(2+)-channel blockers after MI is an effective strategy for treating MI.
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Ácido Azetidinocarboxílico/análogos & derivados , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Infarto do Miocárdio/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Ácido Azetidinocarboxílico/farmacologia , Northern Blotting , Quimiocina CCL2/genética , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Ecocardiografia , Expressão Gênica/efeitos dos fármacos , Gliceraldeído-3-Fosfato Desidrogenases/genética , Masculino , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/genética , Tamanho do Órgão/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The circulating endothelial progenitor cells (EPCs) have an important role in angiogenesis, and the smooth muscle progenitor cells (SMPCs) participate in atherosclerosis. However, little is known about the effects of treatment of diabetes mellitus (DM) on EPCs and SMPCs. Therefore, we investigated the relations between the number of circulating vasucular progenitor cells before and after the treatment for DM. Ten previously untreated DM patients were enrolled in this study. Blood samples were collected before and after treatment. The peripheral mononuclear cells were purified and cultured to differentiate them into EPCs and SMPCs. After two weeks, the number of EPCs was determined by Dil-labeled acetylated low density lipoprotein and lectin binding. The number of SMPCs was evaluated by immunocytochemical staining of alpha-smooth muscle actin. Before treatment, the number of EPCs and SMPCs was significantly related to hemoglobin A1c and blood sugar. Serial examination revealed that improvement of glycemic control significantly increased the number of both EPCs and SMPCs. DM reduces the number of circulating EPCs and SMPCs according to its severity, and treatment of DM significantly increases the number of EPCs and SMPCs, which may be involved in angiogenesis and atherosclerosis in diabetes.
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Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Células-Tronco/patologia , Actinas/metabolismo , Adulto , Aterosclerose/patologia , Glicemia/metabolismo , Proliferação de Células/efeitos dos fármacos , Complicações do Diabetes/patologia , Retinopatia Diabética/patologia , Células Endoteliais/patologia , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/uso terapêutico , Imuno-Histoquímica , Insulina/uso terapêutico , Lipoproteínas LDL/metabolismo , Masculino , Neovascularização Patológica/patologia , Pioglitazona , Tiazolidinedionas/uso terapêuticoRESUMO
BACKGROUND: Activation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinases (JNKs), extracellular signal-regulated kinases (ERKs), and p38MAPK during acute cardiac rejection is not clear. This study aimed to determine whether MAPKs and transcriptional factors such as activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) were involved in acute rejection after cardiac transplantation. METHODS: Hearts from Lewis (LEW) rats (group C) or DA rats (group R) were transplanted into the abdomen of recipients (LEW). Grafts were collected at the 1st, 3rd, or 5th postoperative day (POD). ERKs were measured by Western blot analysis, and JNKs were measured by in-gel kinase assay. AP-1 and NF-kappaB DNA binding activities were determined using an electrophoretic mobility shift assay. We assessed functions of donor hearts using echocardiography. RESULTS: Heart rates and myocardial contraction significantly decreased at POD 5 in group R. Phosphorylated p42ERK and p44ERK in the left ventricular free wall (FW) and septal wall (SW) of group R significantly increased at POD 5 compared to those of group C at POD 1. Activities of p46JNK and p55JNK in the FW and SW of group R also significantly increased at POD 5. AP-1 DNA binding activities in the FW and SW of group R significantly increased at POD 5, and NF-kappaB DNA binding activities of group R significantly increased at PODs 3 and 5. CONCLUSIONS: We conclude that ERK, JNK, AP-1, and NF-kappaB are activated during acute rejection. The MAPK pathways may play an important role in acute cardiac rejection.
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MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Rejeição de Enxerto/etiologia , Transplante de Coração/efeitos adversos , NF-kappa B/fisiologia , Fator de Transcrição AP-1/fisiologia , Animais , Rejeição de Enxerto/fisiopatologia , Frequência Cardíaca/fisiologia , Transplante de Coração/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Ratos , Ratos Endogâmicos Lew , Ratos Endogâmicos , Transplante HeterotópicoRESUMO
Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or alpha-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells.
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Células Endoteliais/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Imuno-Histoquímica , Lectinas/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipoproteínas LDL/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Pravastatina/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia. The purpose of this study was to examine the effects of EPO on cardiac remodeling after myocardial infarction (MI). MI was induced by ligation of the coronary artery in Wistar rats. The rats with MI were randomly divided into untreated MI and two EPO-treated MI groups. EPO was administered subcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 times a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the increase in activated caspase 3, matrix metalloproteinase-2, and transcriptional activation of activator protein-1 in non-infarcted myocardium. Four weeks after MI, left ventricular weight, left ventricular end-diastolic pressure, and left ventricular dimension were increased, and ejection fraction and E wave deceleration time were decreased. EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction. In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium. Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis.
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Eritropoetina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Northern Blotting , Western Blotting , Caspase 3 , Caspases/metabolismo , Modelos Animais de Doenças , Ecocardiografia Doppler , Marcação In Situ das Extremidades Cortadas , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Ratos , Ratos Wistar , Proteínas Recombinantes , Fator de Transcrição AP-1/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/fisiologiaRESUMO
To extend organ preservation time, we attempted to establish a unique method of maintaining a preservation solution in a stable unfrozen state below its freezing point by pressurizing the solution. Livers removed from Lewis rats (RT1l) were stored in UW solution pressurized at the prescribed pressure. After the termination of preservation, orthotopic liver transplantation was performed. Experiment 1: Liver grafts were pressurized up to 30, 40, 50, and 70 MPa and preserved at 0 degrees C for 60 min. Experiment 2: Liver grafts were compressed at a rate of 1.32 or 0.04 MPa/s to 35 MPa and preserved for 60 min at 0 degrees C. Experiments 3 and 4: Liver grafts were pressurized up to 5, 10, 20, and 30 MPa and preserved at -2 degrees C (Exp. 3), -3 degrees C or -4 degrees C (Exp. 4) for 5 h. All rats transplanted with livers pressurized up to 30 MPa (Exp. 1), all rats in the 5 MPa and control groups at -2 degrees C (Exp. 3), and all rats in the 5 MPa group at -3 degrees C (Exp. 4) survived for 2 weeks. In light microscopy, diffuse hemorrhage and vacuolar degeneration of hepatocytes were observed in a pressure-dependent manner. Liver grafts preserved under pressurized, subzero nonfrozen condition have sufficient function to sustain the life of rats after orthotopic transplantation.
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Transplante de Fígado/métodos , Fígado , Preservação de Órgãos/métodos , Pressão , Animais , Criopreservação/métodos , Sobrevivência de Enxerto , Masculino , Microscopia , RatosRESUMO
Antecedent hypertension adversely affects mortality and heart failure after myocardial infarction (MI). In addition, accelerated ventricular remodeling is a contributor to the increased mortality observed after MI. The purpose of this study was to assess the relationship of antecedent hypertension to ventricular remodeling after MI. Ninety-four patients presenting with a first acute MI who were treated with reperfusion therapy within 12 h of their symptom onset were enrolled in this study. All of them underwent left ventriculography immediately after reperfusion therapy and again at 6 months after the occurrence of MI. Patients were divided into two groups: a hypertensive group and a normotensive group. End-diastolic volume index (EDVI), end-systolic volume index (ESVI), and ejection fraction (EF) values in the acute phase were compared to those at 6 months after acute MI in either group. The hypertensive group showed a significant increase in both EDVI and ESVI after 6 months, whereas the normotensive group did not. In addition, there was no change in EF in the hypertensive group, whereas EF increased significantly after 6 months in the normotensive group. As a result, the percent changes in ESVI and EF were significantly different between the hypertensive group and normotensive group. The results demonstrated that antecedent hypertension interacts with ventricular cavity dilatation after MI.
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Hipertensão/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular , Idoso , Feminino , Seguimentos , Humanos , Hipertensão/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Revascularização Miocárdica , Recuperação de Função Fisiológica , Fatores de Risco , Disfunção Ventricular Esquerda/epidemiologiaRESUMO
OBJECTIVE: Rapamycin-coated stents in coronary artery lesions have recently been shown to be effective in inhibiting neointimal formation. However, little is known about the effects of rapamycin on mitogen-activated protein kinase (MAPK), which is an important signal for neointimal formation. Therefore, we examined the effects of rapamycin on MAPK and transcriptional factors in cultured human coronary artery smooth muscle cells (CASMC) and in balloon-injured rat carotid arteries. METHODS AND RESULTS: Activation of ERK, JNK, p38MAPK, AP-1, and NF-kB in coronary artery smooth muscle cells was increased by 2% fetal bovine serum. Ten nmol/L of rapamycin prevented the activation of JNK, p38MAPK, AP-1, and NF-kB (65%, 65%, 67%, and 26% respectively, P<0.01). In an in vivo study, remarkable neointimal formation was observed 14 days after injury. Coating Pluronic gel with 20 and 50 mug rapamycin around the injured artery significantly decreased the intimal area/medial area ratio, compared with vehicle (0.75 vs. 1.2, P<0.01). Rapamycin prevented the increase in activation of JNK, p38MAPK, AP-1, and NF-kB in injured artery (42%, 70%, 75%, and 60% respectively, P<0.05). CONCLUSIONS: Neointimal formation after balloon injury is inhibited by rapamycin, which is partially mediated by inhibition of JNK and p38MAPK, followed by AP-1 and NF-kB.
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Artéria Carótida Primitiva/efeitos dos fármacos , Imunossupressores/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sirolimo/farmacologia , Túnica Íntima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/metabolismo , Artéria Carótida Primitiva/enzimologia , Artéria Carótida Primitiva/metabolismo , Proliferação de Células/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/enzimologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição AP-1/metabolismo , Túnica Íntima/enzimologia , Túnica Íntima/metabolismoRESUMO
Because granulocyte-colony stimulating factor (G-CSF) mobilizes bone marrow cells including endothelial progenitor cells, we examined whether G-CSF augments angiogenesis and collateral vessel formation induced by bone marrow-mononuclear cells transplantation (BMT). Unilateral hindlimb ischemia was surgically induced in Lewis rats. One week after surgery, administration of 100 mg/kg per day G-CSF significantly increased the laser Doppler blood perfusion index (LDBPI), number of angiographically detectable collateral vessels (angiographic score), and capillary density determined by alkaline phosphatase staining. In the BMT group (1 x 10(7) cells/rat) and the group with combined G-CSF treatment and BMT, LDBPI was significantly increased compared with that in the vehicle-treated group. In the BMT group, neovascularization was significantly increased as evidenced by the angiographic score and capillary density compared with the vehicle-treated group. Furthermore, the combination of G-CSF treatment and BMT augmented neovascularization compared with BMT alone, as evidenced by the angiographic score and capillary density. Moreover, G-CSF significantly increased vascular endothelial growth factor mRNA and fibroblast growth factor-2 mRNA in hindlimb muscle. In conclusion, G-CSF was found to augment neovascularization in rat hindlimb ischemia. Combined use of G-CSF treatment and BMT may be a useful strategy for therapeutic neovascularization in ischemic tissues.
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Indutores da Angiogênese/farmacologia , Transplante de Medula Óssea , Fator Estimulador de Colônias de Granulócitos/farmacologia , Membro Posterior/irrigação sanguínea , Isquemia/terapia , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica/efeitos dos fármacos , Fosfatase Alcalina/análise , Angiografia , Animais , Proliferação de Células/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Isquemia/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos Lew , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Osteopontin has been reported to have an important role in cardiac fibrosis. However, little is known about the effects of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blockers (ARB) on osteopontin expression in infarcted myocardium. The purpose of this study was to elucidate the effects of an ACEI (perindpril) and an ARB (candesartan cilexitil) on cardiac function as assessed by Doppler echocardiography and cardiac osteopontin expression associated with cardiac remodeling in myocardial infarcted rats. ACEI or ARB was administered after myocardial infarction (MI). At 4 weeks after MI, cardiac function, and mRNAs in non-infarcted myocardium were analyzed. ACEI and ARB equally prevented left ventricular dilatation, reduction of ejection fraction, and the increase in E/A wave velocity ratio and the rate of E wave deceleration by MI. ACEI and ARB significantly suppressed increased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, osteopontin, and collagen I and III in the non-infarcted ventricle at 4 weeks. Immunohistochemically stained osteopontin was increased in interstitial fibrosis of non-infarcted myocardium. Both ACEI and ARB significantly prevented cardiac fibrosis and osteopontin expression. In conclusion, angiotensin blockade inhibits osteopontin expression in non-infarcted myocardium and prevents cardiac remodeling after MI.
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Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Sialoglicoproteínas/genética , Tetrazóis/farmacologia , Animais , Quimiocina CCL2/genética , Ecocardiografia Doppler , Masculino , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Osteopontina , Perindopril/farmacologia , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Mensageiro/análise , Ratos , Ratos Wistar , Remodelação VentricularRESUMO
OBJECTIVE: We first examined the role of apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, in ischemia-induced angiogenesis. METHODS AND RESULTS: Unilateral hindlimb ischemia was induced surgically in C57BL/6J wild-type (WT) mice or mice deficient in ASK1 (ASK1(-/-)). ASK1 activity in WT mouse hindlimb was increased dramatically after ischemia. By laser Doppler analysis, well-developed collateral vessels and angiogenesis were observed in WT mice in response to hindlimb ischemia, whereas these responses were reduced in ASK1(-/-) mice. Immunostaining revealed that infiltration of macrophages and T lymphocytes was suppressed in the ischemic tissues of ASK1(-/-) mice compared with WT mice. The expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) proteins in ischemic tissues was weaker in ASK1(-/-) mice compared with WT mice. In vitro study on endothelial cells indicated that dominant-negative ASK1 significantly attenuated hydrogen peroxide-induced VEGF and MCP-1 production. Furthermore, in vivo blockade of MCP-1 by its neutralizing antibody suppressed the recovery of the blood flow and capillary formation after ischemia. CONCLUSIONS: ASK1 pathway promotes early angiogenesis by inducing inflammatory cell infiltration and VEGF and MCP-1 expression. ASK1 may provide the basis for the development of new therapeutic strategy for angiogenesis.
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Isquemia/imunologia , Isquemia/metabolismo , MAP Quinase Quinase Quinase 5/genética , MAP Quinase Quinase Quinase 5/metabolismo , Neovascularização Fisiológica/fisiologia , Animais , Capilares/fisiologia , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Membro Posterior/irrigação sanguínea , Humanos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linfócitos T/imunologia , Veias Umbilicais/citologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: Vascular endothelial growth factor (VEGF) plays an important role in inducing angiogenesis. Mesenchymal stem cells (MSCs) may have potential for differentiation to several types of cells, including myocytes. We hypothesized that transplantation of VEGF-expressing MSCs could effectively treat acute myocardial infarction (MI) by providing enhanced cardioprotection, followed by angiogenic effects in salvaging ischemic myocardium. METHODS AND RESULTS: The human VEGF165 gene was transfected to cultured MSCs of Lewis rats using an adenoviral vector. Six million VEGF-transfected and LacZ-transfected MSCs (VEGF group), LacZ-transfected MSCs (control group), or serum-free medium only (medium group) were injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. At 1 week after MI, MSCs were detected by X-gal staining in infarcted region. High expression of VEGF was immunostained in the VEGF group. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in the VEGF group, compared with the medium group. Immunohistochemically, alpha-smooth muscle actin-positive cells were most increased in the VEGF group. CONCLUSIONS: This combined strategy of cell transplantation with gene therapy could be a useful therapy for the treatment of acute MI.