Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension

Abstract

The formation of neointimal lesions is one of the characteristic pathological alterations of the pulmonary vasculature in response to sustained pulmonary arterial hypertension (PAH). To date, the effect of dichloroacetate (DCA) on these intimal lesions had remained to be investigated. In the present study, the beneficial impact of DCA on the formation of neointimal lesions was examined in rats treated with monocrotaline following pneumonectomy. The rats were subjected to monocrotaline subcutaneous injection seven days following left pneumonectomy and received DCA by gastric gavage (80 mg/kg/day) for 20 days. At the end of the experiments, hemodynamic measurement was performed prior to the excision of the rats' right lungs for further morphometric and immunoblot analysis. Furthermore, the activity of reactive oxygen species (ROS), superoxide dismutase (SOD) in the lungs was examined by a colorimetric assay. The results revealed that DCA treatment from day 8-28 following pneumonectomy caused a marked reduction in pulmonary arterial pressure and amelioration in right ventricle hypertrophy (mean pulmonary arterial pressure, 24±2.8 vs. 33±5.5 mmHg; right ventricle-to-left ventricle + intra-ventricle septum ratio, 29±2.8 vs. 43±3.3%; P<0.05) and pulmonary arterioles intimal proliferation (grade 1 and 2 occlusion, 24 and 20% vs. 44 and 40%; P<0.05) in pulmonary hypertensive rats. By contrast, DCA treatment initiated 29 days following pneumonectomy did not result in any improvement in pulmonary circulatory parameters or regression of occlusive neointimal lesions. Immunohistochemical and immunoblot assays demonstrated markedly reduced hypoxia inducible factor (HIF-1α) levels, and increased voltage-dependent potassium channel subtype 1.5 (Kv1.5) expression levels were observed in those neointimal regions in rats receiving DCA preventive therapy. Furthermore, preventive treatment with DCA significantly increased the activity of copper/zinc superoxide dismutase (Cu/Zn SOD activity, 88±4.2 vs. 53±2.7 U/mgprot; P<0.05) and promoted the degradation of ROS (106±4.7 vs. 79±13.3 U/mgprot; P<0.05), which was compromised in the delayed intervention group. Therefore, DCA is effective to prevent the formation of intimal lesions, which may be attributed to the induction of the upregulation of Cu/Zn SOD activity and the suppression of HIF-1α activation.