Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn

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• 作者：Kathryn N. Farrow ; Stephen Wedgwood ; Keng Jin Lee ; Lyubov Czech ; Sylvia F. Gugino ; Satyan Lakshminrusimha ; Paul T. Schumacker ; Robin H. Steinhorn
• 关键词：Pulmonary vasculature ; Reactive oxygen species ; Phosphodiesterase ; cGMP ; Hyperoxia
• 刊名：Respiratory Physiology & Neurobiology
• 出版年：2010
• 出版时间：31 December 2010
• 年：2010
• 卷：174
• 期：3
• 页码：272-281
• 全文大小：1068 K

文摘

In the pulmonary vasculature, phosphodiesterase-5 (PDE5) degrades cGMP and inhibits nitric oxide-mediated, cGMP-dependent vasorelaxation. We previously reported that ventilation with 100 % O₂ increased PDE5 activity in pulmonary arteries (PAs) of pulmonary hypertension lambs (PPHN) more than in control lambs. In the present study, PA smooth muscle cells (PASMCs) from PPHN lambs had increased basal PDE5 activity, decreased cGMP-responsiveness to NO, and increased mitochondrial matrix oxidant stress compared to control PASMC. Hyperoxia (24 h) increased PDE5 activity and mitochondrial matrix oxidant stress above baseline to a similar degree in PPHN and control PASMC. Mitochondrially targeted catalase decreased PDE5 activity at baseline and after hyperoxia in PPHN PASMC. Similarly, catalase treatment of PPHN lambs ventilated with 100 % O₂ decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H₂O₂ is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN.