RESUMEN
Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO2) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO2 treatment. Moreover, OA-NO2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO2. In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO2.Our results show that the oleic acid nitroalkene derivative OA-NO2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO2 represents a potential therapeutic agent for the treatment of PAH.
Asunto(s)
Modelos Animales de Enfermedad , Hipertensión Pulmonar/prevención & control , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/fisiopatología , Inflamación/prevención & control , Ácidos Oléicos/uso terapéutico , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cromatografía Líquida de Alta Presión , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipertensión Pulmonar Primaria Familiar , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Inflamación/etiología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxidos/metabolismoRESUMEN
The incidence of preeclampsia associated maternal and neonatal hyponatremia is reportedly rare and can be life threatening in severe cases. The timely diagnosis and careful management requires a multidisciplinary approach between obstetric, neonatal, endocrinology, and intensive care teams. We report firstly, on a case of severe hyponatremia associated with preeclampsia, secondary to inappropriate Anti-Diuretic Hormone secretion, followed by a review of cases over a one year period at our institution.