Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 292, Issue 6, Pages L1459-L1466Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00143.2006
Keywords
vein; small interfering RNA
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Funding
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL075187, R01HL059435] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL-75187, HL-59435] Funding Source: Medline
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Chronic hypoxia triggers pulmonary vascular remodeling, which is associated with a modulation of the vascular smooth muscle cell ( SMC) phenotype from a contractile, differentiated to a synthetic, dedifferentiated state. We previously reported that acute hypoxia represses cGMP- dependent protein kinase ( PKG) expression in ovine fetal pulmonary venous SMCs ( FPVSMCs). Therefore, we tested if altered expression of PKG could explain SMC phenotype modulation after exposure to hypoxia. Hypoxia- induced reduction in PKG protein expression strongly correlated with the repressed expression of SMC phenotype markers, myosin heavy chain ( MHC), calponin, vimentin, alpha-smooth muscle actin ( alpha SMA), and thrombospondin ( TSP), indicating that hypoxic exposure of SMC induced phenotype modulation to dedifferentiated state, and PKG may be involved in SMC phenotype modulation. PKG- specific small interfering RNA ( siRNA) transfection in FPVSMCs significantly attenuated calponin, vimentin, and MHC expression, with no effect on alpha SMA and TSP. Treatment with 30 mu M Drosophila Antennapedia ( DT- 3), a membrane- permeable peptide inhibitor of PKG, attenuated the expression of TSP, MHC, alpha SMA, vimentin, and calponin. The results from PKG siRNA and DT-3 studies indicate that hypoxia- induced reduction in protein expression was also similarly impacted by PKG inhibition. Overexpression of PKG in FPVSMCs by transfection with a full- length PKG construct tagged with green fluorescent fusion protein ( PKG- GFP) reversed the effect of hypoxia on the expression of SMC phenotype marker proteins. These results suggest that PKG could be one of the determinants for the expression of SMC phenotype marker proteins and may be involved in the maintenance of the differentiated phenotype in pulmonary vascular SMCs in hypoxia.
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