Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery
Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery
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DOI：
10.1152/ajplung.00002.2012
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发表时间：
2012-07-01
影响因子：
4.9
通讯作者：
Gupte, Sachin A.
中科院分区：
文献类型：
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作者：
Chettimada, Sukrutha;Rawat, Dhwajbahadur K.;Gupte, Sachin A.
Chettimada S，Rawat DK，Dey N，Kobelja R，Simms Z，Wolin MS，林肯TM，Gupte SA. Glc-6-PD和PKG参与低氧诱导的肺动脉平滑肌细胞收缩表型蛋白的减少。Am J Physiol Lung Cell Mol Physiol 303：L64-L74，2012.首次发表于2012年5月11日; doi：10.1152/ajplung.00002.2012.-持续性缺氧性肺血管收缩（HPV）在肺动脉高压的发病机制中起重要作用，肺动脉高压是一个全球性的临床问题。我们最近发现，缺氧诱导的肺动脉平滑肌中葡萄糖-6-磷酸脱氢酶（Glc-6-PD）的激活将平滑肌细胞内的代谢变化与HPV联系起来，并且抑制Glc-6-PD可减少急性HPV。在这里，我们证明了在体外将肺动脉环暴露于缺氧（20-30 Torr）12小时显著（P < 0.05）降低（30-50%）SM 22 α和平滑肌肌球蛋白重链表达并诱发HPV。Glc-6-PD活性在缺氧肺动脉中也升高。抑制Glc-6-PD活性可防止缺氧诱导的SM 22 α表达降低，并抑制HPV 80-90%（P < 0.05）。此外，Glc-6-PD和蛋白激酶G（PKG）在肺动脉中形成复合物，并且Glc-6-PD抑制增加PKG介导的VASP磷酸化（p-VASP）。反过来，增加PKG活性上调SM 22 α表达并减弱Glc-6-PD抑制引起的HPV。在低氧动脉中增加被动张力（从0.8至3.0 g）12 h可降低Glc-6-PD，增加p-VASP和SM 22 α水平，并抑制HPV。目前的研究结果表明，葡萄糖-6-PD活性的增加影响PKG活性和平滑肌细胞表型蛋白，所有这些都影响肺动脉收缩性和重塑。
Chettimada S, Rawat DK, Dey N, Kobelja R, Simms Z, Wolin MS, Lincoln TM, Gupte SA. Glc-6-PD and PKG contribute to hypoxia-induced decrease in smooth muscle cell contractile phenotype proteins in pulmonary artery. Am J Physiol Lung Cell Mol Physiol 303: L64-L74, 2012. First published May 11, 2012; doi:10.1152/ajplung.00002.2012.-Persistent hypoxic pulmonary vasoconstriction (HPV) plays a significant role in the pathogenesis of pulmonary hypertension, which is an emerging clinical problem around the world. We recently showed that hypoxia-induced activation of glucose-6-phosphate dehydrogenase (Glc-6-PD) in pulmonary artery smooth muscle links metabolic changes within smooth muscle cells to HPV and that inhibition of Glc-6PD reduces acute HPV. Here, we demonstrate that exposing pulmonary arterial rings to hypoxia (20-30 Torr) for 12 h in vitro significantly (P < 0.05) reduces (by 30-50%) SM22 alpha and smooth muscle myosin heavy chain expression and evokes HPV. Glc-6-PD activity was also elevated in hypoxic pulmonary arteries. Inhibition of Glc-6-PD activity prevented the hypoxia-induced reduction in SM22 alpha expression and inhibited HPV by 80-90% (P < 0.05). Furthermore, Glc-6-PD and protein kinase G (PKG) formed a complex in pulmonary artery, and Glc-6-PD inhibition increased PKG-mediated phosphorylation of VASP (p-VASP). In turn, increasing PKG activity upregulated SM22 alpha expression and attenuated HPV evoked by Glc-6-PD inhibition. Increasing passive tension (from 0.8 to 3.0 g) in hypoxic arteries for 12 h reduced Glc-6-PD, increased p-VASP and SM22 alpha levels, and inhibited HPV. The present findings indicate that increases in Glc-6-PD activity influence PKG activity and smooth muscle cell phenotype proteins, all of which affect pulmonary artery contractility and remodeling.