Effective treatment of vascular endothelial growth factor refractory hindlimb ischemia by a mutant endothelial nitric oxide synthase gene.

Qian, H S; Liu, P; Huw, L-Y; Orme, A; Halks-Miller, M; Hill, S M; Jin, F; Kretschmer, P; Blasko, E; Cashion, L; Szymanski, P; Vergona, R; Harkins, R; Yu, J; Sessa, W C; Dole, W P; Rubanyi, G M; Kauser, K

Qian, H S; Liu, P; Huw, L-Y; Orme, A; Halks-Miller, M; Hill, S M; Jin, F; Kretschmer, P; Blasko, E; Cashion, L; Szymanski, P; Vergona, R; Harkins, R; Yu, J; Sessa, W C; Dole, W P; Rubanyi, G M; Kauser, K.

Afiliación

Qian HS; Department of Pharmacology, Berlex Biosciences, Richmond, CA, USA.

Gene Ther ; 13(18): 1342-50, 2006 Sep.

Article en En | MEDLINE | ID: mdl-16642030

RESUMEN

Gene delivery of angiogenic growth factors is a promising approach for the treatment of ischemic cardiovascular diseases. However, success of this new therapeutic principle is hindered by the lack of critical understanding as to how disease pathology affects the efficiency of gene delivery and/or the downstream signaling pathways of angiogenesis. Critical limb ischemia occurs in patients with advanced atherosclerosis often exhibiting deficiency in endothelial nitric oxide production. Similar to these patients, segmental femoral artery resection progresses into severe ischemic necrosis in mice deficient in endothelial nitric oxide synthase (ecNOS-KO) as well as in balb/c mice. We used these models to evaluate the influence of severe ischemia on transfection efficiency and duration of transgene expression in the skeletal muscle following plasmid injection in combination with electroporation. Subsequently, we also explored the potential therapeutic effect of the phosphomimetic mutant of ecNOS gene (NOS1177D) using optimized delivery parameters, and found significant benefit both in ecNOS-KO and balb/c mice. Our results indicate that NOS1177D gene delivery to the ischemic skeletal muscle can be efficient to reverse critical limb ischemia in pathological settings, which are refractory to treatments with a single growth factor, such as vascular endothelial growth factor.

Asunto(s)

Terapia Genética/métodos; Isquemia/terapia; Músculo Esquelético/metabolismo; Óxido Nítrico Sintasa de Tipo III/genética; Transfección/métodos; Factor A de Crecimiento Endotelial Vascular/metabolismo; Animales; Electroporación; Endotelio Vascular/metabolismo; Expresión Génica; Vectores Genéticos; Miembro Posterior; Humanos; Isquemia/metabolismo; Isquemia/patología; Flujometría por Láser-Doppler; Masculino; Ratones; Ratones Endogámicos BALB C; Ratones Endogámicos C57BL; Ratones Noqueados; Músculo Esquelético/patología; Neovascularización Fisiológica; Óxido Nítrico/metabolismo; Óxido Nítrico Sintasa de Tipo III/análisis; Óxido Nítrico Sintasa de Tipo III/metabolismo; Flujo Sanguíneo Regional; Transgenes; Vasodilatación

Buscar en Google

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transfección / Terapia Genética / Músculo Esquelético / Factor A de Crecimiento Endotelial Vascular / Óxido Nítrico Sintasa de Tipo III / Isquemia Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Gene Ther Asunto de la revista: GENETICA MEDICA / TERAPEUTICA Año: 2006 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

Buscar en Google

Añadir a Mi BVS

Imprimir

XML

PubMed Links