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Archives of cardiovascular diseases
Volume 102, n° S1
page 28 (mars 2009)
Doi : 10.1016/S1875-2136(09)72193-X
Themes et posters

C006 Nadph-oxidases and uncoupled endothelial NO-synthase in pulmonary arterial hypertension induced by chronic hypoxia

E. Delannoy 1, V. Leblais 1, A. Courtois 1, A.-P. Gadeau 2, C. Desgranges 2, E. Closs 3, H. Li 3, R. Marthan 1, B. Muller 1
1 Inserm U885, Université Bordeaux 2, Bordeaux, France 
2 Inserm U828, Pessac, France 
3 Dpt Pharmacologie, Université De Johannes Gutenberg, Mainz, Germany 


Nitric oxide (NO) production by endothelial NO-synthase (eNOS) is critically dependent on the cofactor, tetrahydrobiopterin (BH4). Depletion in BH4 consecutive to an increase of reactive oxygen species (ROS) production by NADPH-oxidases and/or eNOS over-expression, favour eNOS uncoupling. This study investigates the potential role of NADPH-oxidases and uncoupled eNOS in pulmonary arterial hypertension induced by chronic hypoxia.

Male C57BL/6 and eNOS knockout (eNOS-/-) mice were exposed or not to hypobaric hypoxia (0.5atm) for 21 days. Fulton index (right ventricular / left ventricular + septum weight ratio) was determined. Lungs were used for measurement of BH4 (by HPLC), for expression of eNOS (by western-blotting) and of the NADPH-oxidases subunits Nox1, Nox2 and Nox4 (by RT-PCR). Pulmonary arteries were also mounted in a wire myograph for evaluation of vasomotor responses.

Chronic hypoxia induced a marked up-regulation of Nox1, Nox2 and Nox4 mRNAs in lungs, and an increase of ROS levels in pulmonary arteries. BH4 levels, as well as eNOS expression, were enhanced in lungs from hypoxic WT mice (1.25 and 4 fold increase compared to normoxic WT mice, respectively). In pulmonary arteries from hypoxic WT mice, the contractile response to phenylephrine was about 1.8 greater than in those from normoxic WT mice. The use of ROS scavengers (PEG-SOD or catalase) and NOS inhibitor (L-NAME) revealed the involvement of ROS in hypoxia-induced hyper-reactivity to phenylephrine, and a loss of NO-dependent relaxation. Chronic treatment of hypoxic WT mice with the BH4 precursor sepiapterin preserved the vasorelaxant effect of NO. This treatment and the deletion of eNOS gene abolished the inhibitory effect of catalase on phenylephrine-induced contraction, and also attenuated hypoxia-induced right ventricular hypertrophy.

These data show that chronic hypoxia induced an up-regulation of Nox isoforms and eNOS in lungs. They suggest that uncoupled eNOS participates to right ventricular hypertrophy and to alterations of vasomotor responses in pulmonary arteries in hypoxia-induced pulmonary hypertension. The weak increase in BH4 and the large over-expression of eNOS suggest the existence of compensatory mechanisms on BH4 synthesis, which may moderate eNOS dysfunction.

Grants: Fondation de France, ANR, GRRC (E.D PhD grant)

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