RESUMEN
Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.
Asunto(s)
Animales , Masculino , Femenino , Embarazo , Organofosfatos/metabolismo , Polímeros/metabolismo , Canal de Potasio Kv1.5/análisis , Hipoxia Fetal/complicaciones , Hipoxia Fetal/fisiopatología , Retardo del Crecimiento Fetal/metabolismo , Hipertensión Pulmonar/etiología , Músculo Liso Vascular/química , Fosforilación , Efectos Tardíos de la Exposición Prenatal/metabolismo , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/patología , Factores de Tiempo , ARN Mensajero/análisis , Inmunohistoquímica , Immunoblotting , Distribución Aleatoria , Regulación hacia Arriba , Técnica del Anticuerpo Fluorescente , Ratas Sprague-Dawley , Desnutrición/complicaciones , Modelos Animales de Enfermedad , Retardo del Crecimiento Fetal/etiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/patología , Músculo Liso Vascular/patologíaRESUMEN
The study is to investigate the effect of anti-caspase treatment on anti-chlamydia immune response in mice. Both the humoral and aspects of cell-mediated immune response against Chlamydia trachomatis were studied. Antibody response was measured using the ELISA technique to identify all common isotypes, and cytokine response was measured using the PCR technique. The antibody levels (IgG, IgG1, IgG2a and IgA) in Z-VAD-FMK treated group were significantly higher than non-treated group. ELISA results [showed a significantly higher amount of antibodies (IgG, IgG1, Ig G2a and IgA)] were produced in the mice that were pre-treated with Z-VAD-FMK before infection with Chlamydia trachomatis compared to mice post treated with Z-VAD-FMK after Chlamydia trachomatis infection. Data of the study indicate that the caspase inhibitor, Z-VAD-FMK did not negatively affect humoral and T cell mediated immune responses against C. trachomatis in mice.