ABSTRACT
BACKGROUND: Stem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI). METHODS: The influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation. RESULTS: SDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with p240MSC, SDF1αMSC, and VEGF-A165MSC in comparison to the control group. CONCLUSIONS: These findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function.
Subject(s)
Chemokine CXCL12/administration & dosage , Mesenchymal Stem Cells/drug effects , Myocardial Infarction/therapy , Neovascularization, Physiologic/drug effects , Animals , Cells, Cultured , Male , Mesenchymal Stem Cells/physiology , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/physiopathology , Neovascularization, Physiologic/physiology , Rats , Rats, Wistar , Recombinant Proteins/administration & dosageABSTRACT
Gene therapy holds great promise as a targeted treatment of cardiovascular diseases, which remain a major cause of morbidity and mortality in contemporary societies. Selection of the appropriate vector delivery method is critical for efficient transduction in the myocardium. Direct myocardial delivery is a feasible and effective method that has been shown to exhibit enhanced gene expression compared to coronary infusion and pericardial delivery. It is one of the most widely used gene transfer methods in both animal studies and clinical trials. The advantages, which result from a delivery that avoids exposure to the blood and bypasses the endothelial barrier, are a high local concentration at the injection site and a decreased leakage to off-target organs. The vectors are injected either with an endomyocardial or an epicardial approach, either surgically or percutaneously. In this chapter, we present the different approaches of direct myocardial injection, their advantages and their realization method in preclinical large animal models of cardiovascular diseases.
Subject(s)
Genetic Vectors/metabolism , Injections , Myocardium/metabolism , Animals , Fluoroscopy , Pericardium/surgery , Sus scrofaABSTRACT
Objective To evaluate the effect of ultrasound guided via chest puncture injection and ultrasound targeted microbubble destruction(UTMD) mediated the angiogenin 1 (Ang1) gene therapy in myocardial infarction (MI) canines.Methods Thirty nine dogs were divided into three groups (each group 13 dogs):① MI group (MI dogs without treatment);② intravenous injection group (MI dogs with intravenous injection and UTMD treatment);③ myocardial injection group (MI dogs with myocardial injection and UTMD treatment).Four weeks later,the safety and incidence of complications were compared.The dimensions and systolic function of left ventricular were measured by echocardiography.The percentage of collagen fiber was assessed by Masson.CD31 was applied for quantifying capillary density.The Ang1 protein was detected by Western blotting.Results ①The survival and complications showed no significant difference among the 3 groups(allP ＞0.05).②Compared with MI group,the left ventricular end systolic dimension (LVESD)reduced and the left ventricular ejection fraction (LVEF) increased in intravenous injection group;the left ventricular end-diastolic dimension (LVEDD) and LVESD were both reduced in myocardial injection group,the LVEF was increased significantly(all P ＜0.05).③ The immunohistochemistry showed lower collagen fiber percentage and higher blood vessel density in myocardial injection group than those in the other groups(P ＜0.05).④The relative quantity of Ang1 was significantly higher in myocardial injection group than those of the other groups.The differences were statistically significant (P ＜0.05).Conclusions The combination of ultrasound guided via chest puncture injection and UTMD is a safe and effective method for gene transfection.It mediates Ang1 gene transfection that can promote angiogenesis after MI and improve left ventricular systolic function.
ABSTRACT
Os eventos isquêmicos em cães são incomuns, porém podem estar sendo subnotificados. Avaliou-se o infarto agudo do miocárdio (IAM) clinicamente, por meio de eletrocardiografia (ECG), eletrocardiografia contínua (EC), ecocardiografia (ECO), enzima creatina quinase (CK), enzima creatina quinase fração MB (CK-MB) e anátomo-histologicamente em cães sem raça definida, e observou-se a ocorrência de arritmias após injeção intramiocárdia por EC. O IAM foi obtido após a ligadura da coronária descendente anterior. Os animais apresentaram ao ECO dilatação da câmara esquerda e aumento do índice de desempenho miocárdico. Ao ECG houve desnivelamento de ST nas derivações pré-cordiais V1 e V2. No EC observaram-se arritmias ventriculares graves e supradesnivelamento de ST. As enzimas CK e CK-MB aumentaram significativamente, sendo que os picos de CK-MB e de CK ocorreram seis horas e 12 horas, respectivamente, após o IAM. Na análise histológica constatou-se infarto da parede inferior do ventrículo esquerdo e substituição do tecido muscular por tecido fibroso. Avaliou-se a injeção intramiocárdica por EC que pode servir como via terapêutica cardíaca, não sendo observado aumento das arritmias ventriculares após a injeção no miocárdio infartado. O infarto em cães pode ser detectado pelos exames cardíacos disponíveis, e a injeção intramiocárdica é uma via terapêutica cardíaca possível.
Ischemic events in dogs are uncommon; however, this may be under-reported. The myocardial infarction was created by left anterior descending coronary ligation in healthy mongrel dogs in clinical and laboratorial exams. These dogs were evaluated clinically, electrocardiography (ECG), through ambulatory electrocardiography (AE), echocardiography (ECO), creatine kinase enzyme (CK), creatine kinase MB fraction enzyme (CK-MB) and histopathologically. Even in these animals we observed the occurrence of arrhythmia after intramyocardial injection by AE. The animals exhibited left ventricular chamber enlargement and increase in myocardial performance index at ECO. In ECG, there were deviations in ST segment in the precordial leads V1 and V2. CK and CK-MB showed high increase, CK and CK-MB peaks occurred six and 12 hours after infarction, respectively. Histopathology of the infarction in the inferior wall of the left ventricle and replacement of muscle tissue by fibrous tissue were seen. Furthermore, intramyocardial injection that may be used for therapeutic purposes was evaluated by AE, which demonstrated no increase in the ventricular arrhythmias. Therefore, myocardial infarction in dogs can be detected with the tests available and intramyocardial injection can be used as a therapeutic way.
