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.

Activation of endothelial NO synthase by a xanthine derivative ameliorates hypoxia-induced apoptosis in endothelial progenitor cells

“…Our previous studies have shown that KMUP‐1 can exert beneficial effects on various diseases associated with vascular dysfunction . In addition, KMUP‐1 was shown to have protective effects against the hypoxia‐induced injury in pulmonary artery and hepatic tissues. The present study demonstrated for the first time the protective effects of KMUP‐1 on EPCs under hypoxic condition.…”

Crosstalk between Vitamins A, B12, D, K, C, and E Status and Arterial Stiffness

“…Ascorbic acid may reverse impaired endothelium-dependent NO-mediated vasodilation in several conditions, including acute hyperglycemia and chronic renal failure [ 45 , 117 ]. The main mechanisms of NO increase include reduced NO degradation by free radicals considering ascorbic acid, as an extremely potent free radical scavenger, increase of endothelial NO synthase activity, increase in the intracellular content of tetrahydrobiopterin, reduced insulin resistance, or smooth muscle sensitivity to NO [ 45 , 46 , 116 , 118 , 119 ]. Diabetes mellitus is associated with endothelial dysfunction due to several factors, including hyperglycemia, insulin resistance, hyperlipidemia, oxidized LDL and ascorbic acid deficiency (due to an impaired vitamin C recycling), and arterial stiffness [ 46 ].…”