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- 저자 : ( Bahaa Francis ) (검색결과 1 건)
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Slide Session : OS-RES-11 ; Tetrahdrobiopterin(BH4): Novel Treatment for Pulmonary Hypertension
( Bahaa Francis ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1
Background: Pulmonary Hypertension (PH) is characterized by pulmonary vasoconstriction, vascular remodeling, right heart failure and death. The pathogenesis is multifactorial. The integrity of the pulmonary vascular endothelium, particularly its endothelial nitric oxide synthase (eNOS), is a key factor in maintaining normal pulmonary vascular homeostasis. While enzymatically coupled, eNOS produces nitric oxide (NO), otherwise eNOS activation may lead to increased superoxide production. The cofactor tetrahydrobiopterin (BH4) is an important regulator of eNOS function; by ‘recoupling’ eNOS and enhancing its enzymatic activity, BH4 increases NO bioavailability and decreases superoxide production. Thus pharmacological supplementation with BH4 may be a novel treatment in PH. Methods: Isolated perfused lung studies were used to explore the acute pharmacological effects of BH4 in regulating pulmonary vascular tone. Animal studies were used to evaluate the pharmacological effects of BH4 treatment and to clarify its molecular mechanism using biochemical and histological experiments. Results: In acute ex-vivo studies, BH4 was found to regulate hypoxic pulmonary vasoconstriction. Its effects are mediated via enhancing NO and H2O2 secretion and its antioxidant properties, all leading to pulmonary vasodilation. Superoxide dismutase co-administration with BH4 enhanced its vasodilatory effect. In chronic studies, BH4 prevented the development of PH in monocrotaline model and ameliorated established PH when administered to recover the disease. BH4 partially reversed PH in hypoxia model. In both models, BH4 reduced pulmonary vascular muscularization and reversed right ventricular hypertrophy. BH4 effect was evidenced by enhancing the activity and protein levels of eNOS, recoupling eNOS activity to produce more NO, and its second messenger cGMP, and lowering the levels of superoxide. Conclusions: BH4 bioavailability is essential for maintaining pulmonary vascular homeostasis, and plays a major role in the pathophysiology of PH. This study establishes a fi rm basis to explore the therapeutic potential of BH4 in human PH.
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