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À propos de : Postnatal maturational shift from PKCζ and voltage-gated K+ channels to RhoA/Rho kinase in pulmonary vasoconstriction        

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  • Postnatal maturational shift from PKCζ and voltage-gated K+ channels to RhoA/Rho kinase in pulmonary vasoconstriction
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  • Abstract. Objective: The neonate is at high risk of developing pulmonary hypertension, which may reflect a misbalance between vasodilator and vasoconstrictor agents. Thromboxane A2 (TXA2) is involved in several forms pulmonary hypertension, but the signaling pathways mediating its pulmonary vasoconstrictor responses during postnatal maturation have not been analyzed. We therefore investigated the role of L-type Ca2+ channels, protein kinase C (PKC) ζ, voltage-gated K+ channels (KV), and RhoA/Rho kinase in TXA2-induced pulmonary vasoconstriction during postnatal maturation. Methods: Changes in contractility and intracellular calcium were analyzed in 1 day (newborn) and 2-week-old piglets' pulmonary arteries (PA). KV currents were investigated in freshly isolated smooth muscle cells using the whole-cell configuration of the patch clamp technique. Results: The contractile responses to the TXA2 mimetic U46619 were similar at both ages but the L-type Ca2+ channel blocker nifedipine and a PKCζ pseudosubstrate inhibitor only attenuated the contraction in newborn PA. KV currents were similarly inhibited by U46619, although their density was dramatically reduced in 2-week-old as compared to newborn PA smooth muscle cells. This was consistent with a greater contraction to the KV inhibitor, 4-aminopyridine, and with a leftward shift in the increase in intracellular Ca2+ by U46619 in newborn versus older animals. On the other hand, the Rho kinase inhibitor Y-27632 induced a stronger inhibitory effect on the contraction induced by U46619 in 2-week-old than in newborn PA and this was accompanied with minor effects on intracellular calcium levels. Conclusion: TXA2-induced pulmonary vasoconstriction involves PKCζ-KV-L-type Ca2+ channel and RhoA/Rho kinase signaling pathways, which are downregulated and upregulated, respectively, during postnatal maturation. The different contribution of these pathways could be of relevant importance for the vasodilator therapy choice in the treatment of pulmonary hypertension.
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  • 66-1-84
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