title: Buffered 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.
abstract: 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.
authors.affiliation: Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Li-Pin
authors.initials: LP
authors.lastname: Kao
authors.affiliation: Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.affiliation: Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Ya
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Pharmacology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: ingjun@kmu.edu.tw.
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D000068677:Sildenafil Citrate / Q000737:chemistry / Q000627:therapeutic use*; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D014970:Xanthines / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000577:Amides; D010880:Piperidines; D011725:Pyridines; D042442:Vascular Endothelial Growth Factors; D014970:Xanthines; C108830:Y 27632; C439304:KMUP 1; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; D001205:Ascorbic Acid
keywords: Endothelium nitric oxide synthase; Hypoxia; Pulmonary arterial hypertension; Rho kinase II; Vascular endothelium growth factor