Open AccessBuffered l ‐ascorbic acid, alone or bound to KMUP‐1 or sildenafil, reduces vascular endothelium growth factor and restores endothelium nitric oxide synthase in hypoxic pulmonary artery
Author(s) -
Wu JiunnRen,
Kao LiPin,
Wu BinNan,
Dai ZenKong,
Wang YiYa,
Chai CheeYin,
Chen IngJun
Publication year - 2015
Publication title -
the kaohsiung journal of medical sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.439
H-Index - 36
eISSN - 2410-8650
pISSN - 1607-551X
DOI - 10.1016/j.kjms.2015.02.005
Subject(s) - enos , ascorbic acid , medicine , sildenafil , nitric oxide , rho associated protein kinase , hypoxia (environmental) , pulmonary artery , endocrinology , nitric oxide synthase , pharmacology , chemistry , biochemistry , kinase , food science , organic chemistry , oxygen
Ascorbic acid bound to KMUP‐1 and sildenafil were examined for their antioxidant effects on vascular endothelium growth factor (VEGF) and endothelium nitric oxide synthase (eNOS) in hypoxic pulmonary artery (PA). Inhaled KMUP‐1 and oral sildenafil released NO from eNOS. The effect of buffered l ‐ascorbic acid, alone and bound to KMUP‐1 or sildenafil, for treating pulmonary arterial hypertension (PAH) is unclear. In this study, the antioxidant capacity of ascorbic acid increased the beneficial effects of KMUP‐1 on PAH. KMUP‐1A and sildenafil‐A (5 mg/kg/d) were administered to hypoxic PAH rats. Pulmonary artery blood pressure, and VEGF, Rho kinase II (ROCK II), eNOS, soluble guanylate cyclase (sGC‐α), and protein kinase G expression in lung tissues were measured to link PAH and right ventricular hypertrophy. Hypoxic rats had higher pulmonary artery blood pressure, greater PA medial wall thickness and cardiac weight, and a higher right ventricle/left ventricle + septum [RV/(LV+S)] ratio than normoxic rats. Oral KMUP‐1A or sildenafil‐A for 21 days in hypoxia prevented the rarefaction of eNOS in immunohistochemistry (IHC), reduced the IHC of VEGF in PAs, restored eNOS/protein kinase G/phosphodiesterase 5A; unaffected sGC‐α and inactivated ROCK II expression were also found in lung tissues. In normoxic PA, KMUP‐1A/Y27632 (10μM) increased eNOS and reduced ROCK II. ROCK II/reactive oxidative species was increased and eNOS was reduced after long‐term hypoxia for 21 days. KMUP‐1A or Y27632 blunted ROCK II in short‐term hypoxic PA at 24 hours. l ‐Ascorbic acid + l ‐sodium ascorbate (40, 80μM) buffer alone directly inhibited the IHC of VEGF in hypoxic PA. Finally, KMUP‐1A or sildenafil‐A reduced PAH and associated right ventricular hypertrophy.