Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression.
Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression.
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DOI：
10.1152/ajplung.00281.2005
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发表时间：
2006-03
期刊：
影响因子：
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通讯作者：
E. Resnik;J. Herron;M. Keck;David Sukovich;Bradley C. Linden;D. Cornfield
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文献类型：
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作者：
E. Resnik;J. Herron;M. Keck;David Sukovich;Bradley C. Linden;D. Cornfield
出生时肺动脉平滑肌细胞（PASMC）松弛是由于胞浆cGMP增加、cGMP依赖性和激酶介导的Ca 2+敏感性K+通道（KCa）激活以及电压操纵性Ca 2+通道（VOCC）关闭所致。慢性宫内肺动脉高压如何影响围生期肺血管扩张仍不清楚。我们检验了慢性宫内肺动脉高压选择性改变基因表达以减轻cGMP激酶-KCa-VOCC通路介导的围产期肺血管舒张的假设。从妊娠晚期胎羊中分离PASMC，所述胎羊在妊娠127天时进行动脉导管结扎（高血压）或假手术（对照），并在原代培养中维持在低氧（约25 Torr）或常氧（约120 Torr）条件下。我们研究了cGMP激酶I α（PKG-1 α）、VOCC α链（Cav1.2）和KCa通道α亚基的mRNA水平。与对照组相比，高血压组PASMC的VOCC、KCa和PKG-1 α表达降低。在持续常氧条件下，VOCC和KCa通道表达减少，PKG-1 α表达增加。相反，持续常氧对高血压PASMC中PKG-1 α水平没有影响，对VOCC和KCa通道表达的影响减弱。PKG-1 α的蛋白表达与mRNA数据一致。我们的结论是，慢性宫内肺动脉高压降低PKG的表达和减轻持续常氧对肺血管舒张的遗传效应，因为基因表达仍然受到损害，即使在持续暴露于常氧。
Pulmonary artery smooth muscle cell (PASMC) relaxation at birth results from an increase in cytosolic cGMP, cGMP-dependent and kinase-mediated activation of the Ca2+-sensitive K+ channel (KCa), and closure of voltage-operated Ca2+ channels (VOCC). How chronic intrauterine pulmonary hypertension compromises perinatal pulmonary vasodilation remains unknown. We tested the hypothesis that chronic intrauterine pulmonary hypertension selectively modifies gene expression to mitigate perinatal pulmonary vasodilation mediated by the cGMP kinase-KCa-VOCC pathway. PASMC were isolated from late-gestation fetal lambs that had undergone either ligation of the ductus arteriosus (hypertensive) or sham operation (control) at 127 days of gestation and were maintained under either hypoxic (approximately 25 Torr) or normoxic (approximately 120 Torr) conditions in primary culture. We studied mRNA levels for cGMP kinase Ialpha (PKG-1alpha), the alpha-chain of VOCC (Cav1.2), and the alpha-subunit of the KCa channel. Compared with control PASMC, hypertensive PASMC had decreased VOCC, KCa, and PKG-1alpha expression. In response to sustained normoxia, expression of VOCC and KCa channel decreased and expression of PKG-1alpha increased. In contrast, sustained normoxia had no effect on PKG-1alpha levels and an attenuated effect on VOCC and KCa channel expression in hypertensive PASMC. Protein expression of PKG-1alpha was consistent with the mRNA data. We conclude that chronic intrauterine pulmonary hypertension decreases PKG expression and mitigates the genetic effects of sustained normoxia on pulmonary vasodilation, because gene expression remains compromised even after sustained exposure to normoxia.