Document Detail


Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells.
MedLine Citation:
PMID:  24084215     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hypoxia-induced pulmonary hypertension is characterized by progressive remodeling of the pulmonary artery (PA) system and loss of the transcription factor, cAMP response element binding protein (CREB) in PA smooth muscle cells (SMCs). Previous in vitro studies suggested that platelet-derived growth factor, a mitogen produced in the hypoxic arterial wall, elicits loss of CREB in medial SMCs via the PI3K/Akt pathway. These events trigger switching of SMCs from a quiescent, contractile phenotype to a proliferative, migratory, dedifferentiated, and synthetic phenotype, which contributes to PA thickening. Here, we investigated whether inhibition of PI3K or Akt could attenuate arterial remodeling in the lung and prevent CREB loss in PA medial SMCs in rats subjected to chronic hypoxia. Inhibition of either enzyme-blunted hypoxia-induced PA remodeling and SMC CREB depletion and diminished SMC proliferation and collagen deposition. Inhibition of Akt, but not PI3K, suppressed muscularization of distal arterioles and blunted right ventricular hypertrophy. Interestingly, mean PA pressure was elevated equally by hypoxia in untreated and inhibitor-treated groups but was normalized acutely by the Rho kinase inhibitor, Fasudil. We conclude that PI3K and Akt inhibitors can attenuate hypoxia-induced PA remodeling and SMC CREB depletion but fail to block the development of pulmonary hypertension because of their inability to repress Rho kinase-mediated vasoconstriction.
Authors:
Chrystelle V Garat; Joseph T Crossno; Timothy M Sullivan; Jane E B Reusch; Dwight J Klemm
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  62     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-09     Completed Date:  2014-08-20     Revised Date:  2014-08-27    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  539-48     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / physiopathology
Arterioles / drug effects,  metabolism,  pathology
Cell Proliferation / drug effects
Cyclic AMP Response Element-Binding Protein / agonists*,  metabolism
Enzyme Inhibitors / therapeutic use
Extracellular Matrix / drug effects,  metabolism,  pathology
Hypertension, Pulmonary / etiology,  prevention & control*
Hypertrophy, Right Ventricular / etiology,  prevention & control
Male
Muscle, Smooth, Vascular / drug effects*,  metabolism,  pathology
Phosphatidylinositol 3-Kinase / antagonists & inhibitors,  metabolism
Protein Kinase Inhibitors / pharmacology,  therapeutic use*
Protein Stability / drug effects
Proto-Oncogene Proteins c-akt / antagonists & inhibitors,  metabolism
Pulmonary Artery / drug effects*,  metabolism,  pathology
Pulmonary Circulation / drug effects
Rats
Rats, Inbred WKY
Signal Transduction / drug effects*
Vasodilator Agents / pharmacology,  therapeutic use
rho-Associated Kinases / antagonists & inhibitors*,  metabolism
Grant Support
ID/Acronym/Agency:
P01 HL014985/HL/NHLBI NIH HHS; P01-HL014985/HL/NHLBI NIH HHS; R01 DK053969/DK/NIDDK NIH HHS; R01 DK064741/DK/NIDDK NIH HHS; UL1 TR000154/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/CREB1 protein, rat; 0/Cyclic AMP Response Element-Binding Protein; 0/Enzyme Inhibitors; 0/Protein Kinase Inhibitors; 0/Vasodilator Agents; EC 2.7.1.137/Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Akt1 protein, rat; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/rho-Associated Kinases
Comments/Corrections

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