RESUMEN
We examined the effects of overexpressing HSPA12B on angiogenesis and myocardial function by intramyocardial administration of adenovirus encoding HSPA12B (Ad. HSPA12B) in a streptozotocin-induced diabetic rat subjected to myocardial infarction. Rats were divided randomly into six groups: control sham (CS) + Ad.LacZ, control myocardial infarction (CMI) + Ad.LacZ, control MI + Ad.HSPA12B, diabetic sham (DS) + Ad.LacZ, diabetic MI + Ad.LacZ and diabetic MI + Ad.HSPA12B. Following MI or sham surgery, the respective groups received either Ad.LacZ or Ad.HSPA12B via intramyocardial injections. We observed increased capillary and arteriolar density along with reduced fibrosis and preserved heart functions in DMI-AdHSPA12B compared to DMI-AdLacZ group. Western blot analysis demonstrated enhanced HSPA12B, vascular endothelial growth factor (VEGF), thioredoxin-1 (Trx-1) expression along with decreased expression of thioredoxin interacting protein (TXNIP) and A kinase anchoring protein 12 (AKAP12) in the DMI-AdHSPA12B compared to DMI-AdLacZ group. Our findings reveal that HSPA12B overexpression interacts with AKAP12 and downregulate TXNIP in diabetic rats following acute MI.
Asunto(s)
Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diabetes Mellitus Experimental/terapia , Terapia Genética/métodos , Proteínas HSP70 de Choque Térmico/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Infarto del Miocardio/terapia , Disfunción Ventricular Izquierda/prevención & control , Función Ventricular Izquierda , Proteínas de Anclaje a la Quinasa A/genética , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular/genética , Movimiento Celular , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Fibrosis , Regulación de la Expresión Génica , Proteínas HSP70 de Choque Térmico/genética , Humanos , Simulación del Acoplamiento Molecular , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Neovascularización Fisiológica , Unión Proteica , Interferencia de ARN , Ratas Sprague-Dawley , Transducción de Señal , Factores de Tiempo , Transfección , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
INTRODUCTION: Engraftment of mesenchymal stem cells (MSCs) has emerged as a powerful candidate for mediating myocardial repair. In this study, we genetically modified MSCs with an adenovector encoding thioredoxin-1 (Ad.Trx1). Trx1 has been described as a growth regulator, a transcription factor regulator, a cofactor, and a powerful antioxidant. We explored whether engineered MSCs, when transplanted, are capable of improving cardiac function and angiogenesis in a rat model of myocardial infarction (MI). METHODS: Rat MSCs were cultured and divided into MSC, MSC+Ad.LacZ, and MSC+Ad.Trx1 groups. The cells were assayed for proliferation, and differentiation potential. In addition, rats were divided into control-sham (CS), control-MI (CMI), MSC+Ad.LacZ-MI (MLZMI), and MSC+Ad.Trx1-MI (MTrxMI) groups. MI was induced by left anterior descending coronary artery (LAD) ligation, and MSCs preconditioned with either Ad.LacZ or Ad.Trx1 were immediately administered to four sites in the peri-infarct zone. RESULTS: The MSC+Ad.Trx1 cells increased the proliferation capacity and maintained pluripotency, allowing them to divide into cardiomyocytes, smooth muscle, and endothelial cells. Western blot analysis, 4 days after treatment showed increased vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and C-X-C chemokine receptor type 4 (CXCR4). Also capillary density along with myocardial function as examined by echocardiography was found to be increased. Fibrosis was reduced in the MTrxMI group compared to MLZMI and CMI. Visualization of Connexin-43 by immunohistochemistry confirmed increased intercellular connections in the MTrxMI rats compared to MLZMI. CONCLUSION: Engineering MSCs to express Trx1 may prove to be a strategic therapeutic modality in the treatment of cardiac failure.
Asunto(s)
Inductores de la Angiogénesis/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/fisiología , Infarto del Miocardio/terapia , Tiorredoxinas/genética , Animales , Diferenciación Celular , Fibrosis/metabolismo , Terapia Genética/métodos , Hemo-Oxigenasa 1/metabolismo , Masculino , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Células Madre Mesenquimatosas/citología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Neovascularización Fisiológica/fisiología , Ratas , Ratas Sprague-Dawley , Receptores CXCR4/metabolismo , Tiorredoxinas/biosíntesis , Tiorredoxinas/metabolismo , Transfección , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
INTRODUCTION: Tick-borne diseases present a special problem in Connecticut and the Northeastern United States. The tick species Ixodes scapularis known for Lyme disease may also infect humans with anaplasmosis, while other tick species [Amblyomma spp.] may transmit ehrlichiosis. These illnesses may present in various ways depending on the virulence of the organism and variable host factors. CASE PRESENTATION: Our patient presented as a motor vehicle trauma presumably from encephalopathy secondary to anaplasmosis. Unusual features of the patient's case led to the causative diagnosis on peripheral blood smear examination. CONCLUSION: Tick-borne diseases are endemic in Connecticut. The astute clinician should maintain a healthy vigilance for these illnesses. Although our patient presented as a trauma, the presumed precipitating disease could have been treated. Physician awareness and patient education may lessen the impact of these diseases.