Dichloroacetate Inhibits Vascular Remodeling and Increases Voltage-gate K+ Expression in a High-altitude-induced Pulmonary Artery Hypertension Rat Model

Abstract

To investigate the effect of dichloroacetate (DCA) on the mean pulmonary artery pressure (mPAP), pulmonary artery (PA) remodeling and voltage-gate K+ (Kv) channel expression in pulmonary arterial smooth muscle cells (PASMCs) in high altitude-induced pulmonary artery hypertension (HA-PAH) rats. Sprague-Dawley rats were randomly assigned to normal control (N), high altitude (HA), and HA+DCA (70 mg/kg DCA administration daily) groups (n=8 each). Rats were housed in a hypobaric, hypoxic chamber to mimic an altitude of 5000m for 21 days; then the mPAP and the wall thickness (WT) of the PA smooth muscle were measured. PASMCs apoptosis was examined using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stain. Real-time PCR, immunohistochemistry and western blot analyses were carried out to detect Kv1.5 and Kv2.1 expression in PASMCs. The expression of Kv1.5 and Kv2.1 was decreased in HA rats. With DCA treatment, the expression of Kv1.5 and Kv2.1 was restored, and the established HA-PAH was ameliorated. Compared with the HA-PAH rats, the DCA-treated rats displayed a decreased mPAP, WT of the PAs, right ventricular hypertrophy and ([Ca2+]i), and more PASMCs were apoptotic. DCA partially reversed the downregulation of Kv1.5 and Kv2.1 in the PASMCs of HA-PAH rats. DCA can reverse the remodeling of the PA and upregulate Kv1.5 and Kv2.1 expression in the PASMCs of HA-PAH rats. This result suggests that DCA may be an effective drug for treating HA-PAH and that restoring Kv1.5 and Kv2.1 can partially decrease mPAP.