Document Detail

Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation.
MedLine Citation:
PMID:  23043075     Owner:  NLM     Status:  MEDLINE    
High-altitude long-term hypoxia (LTH) is known to induce pulmonary arterial smooth muscle cell (PASMC) proliferation in the fetus, leading to pulmonary arterial remodeling and pulmonary hypertension of the newborn. The mechanisms underlying these conditions remain enigmatic however. We hypothesized that epigenetic alterations in fetal PASMC induced by high-altitude LTH may play an important role in modulating their proliferation during pulmonary arterial remodeling. To test this hypothesis, we have analyzed epigenetic alterations in the pulmonary vasculature of fetal lambs exposed to high-altitude LTH [pregnant ewes were kept at 3,801 m altitude from ~40 to 145 days gestation] or to sea level atmosphere. Intrapulmonary arteries were isolated, and fetal PASMC were cultured from both control and LTH fetuses. Compared with controls, in LTH fetus pulmonary arteries measurements of histone acetylation and global DNA methylation demonstrated reduced levels of global histone 4 acetylation and DNA methylation, accompanied by the loss of the cyclin-dependent kinase inhibitor p21. Treatment of LTH fetal PASMCs with histone deacetylase (HDAC) inhibitor trichostatin A decreased their proliferation rate, in part because of altered expression of p21 at both RNA and protein level. In PASMC of LTH fetuses, HDAC inhibition also decreased PDGF-induced cell migration and ERK1/2 activation and modulated global DNA methylation. On the basis of these observations, we propose that epigenetic alterations (reduced histone acetylation and DNA methylation) caused by chronic hypoxia leads to fetal PASMC proliferation and vessel remodeling associated with vascular proliferative disease and that this process is regulated by p21.
Qiwei Yang; Ziyan Lu; Ramaswamy Ramchandran; Lawrence D Longo; J Usha Raj
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-05
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  303     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L1001-10     Citation Subset:  IM    
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MeSH Terms
Cell Cycle Checkpoints
Cell Movement*
Cell Proliferation* / drug effects
Cell Survival
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
DNA Methylation / drug effects
Epigenesis, Genetic
Fetal Hypoxia / metabolism,  pathology*
Fetus / pathology
Gene Expression
Histone Deacetylase Inhibitors / pharmacology
Histones / metabolism*
Hydroxamic Acids / pharmacology
MAP Kinase Signaling System
Muscle, Smooth, Vascular / metabolism,  pathology*
Myocytes, Smooth Muscle / drug effects,  metabolism,  physiology*
Peptides, Cyclic / pharmacology
Platelet-Derived Growth Factor / physiology
Protein Processing, Post-Translational
Pulmonary Artery / metabolism,  pathology*
Time Factors
Tumor Suppressor Protein p53 / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/Hydroxamic Acids; 0/Peptides, Cyclic; 0/Platelet-Derived Growth Factor; 0/Tumor Suppressor Protein p53; 0/apicidin; 3X2S926L3Z/trichostatin A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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