Document Detail


PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress.
MedLine Citation:
PMID:  23421427     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Vascular injury and chronic arterial diseases result in exposure of VSMCs (vascular smooth muscle cells) to increased concentrations of growth factors. The mechanisms by which growth factors trigger VSMC phenotype transitions remain unclear. Because cellular reprogramming initiated by growth factors requires not only the induction of genes involved in cell proliferation, but also the removal of contractile proteins, we hypothesized that autophagy is an essential modulator of VSMC phenotype. Treatment of VSMCs with PDGF (platelet-derived growth factor)-BB resulted in decreased expression of the contractile phenotype markers calponin and α-smooth muscle actin and up-regulation of the synthetic phenotype markers osteopontin and vimentin. Autophagy, as assessed by LC3 (microtubule-associated protein light chain 3 α; also known as MAP1LC3A)-II abundance, LC3 puncta formation and electron microscopy, was activated by PDGF exposure. Inhibition of autophagy with 3-methyladenine, spautin-1 or bafilomycin stabilized the contractile phenotype. In particular, spautin-1 stabilized α-smooth muscle cell actin and calponin in PDGF-treated cells and prevented actin filament disorganization, diminished production of extracellular matrix, and abrogated VSMC hyperproliferation and migration. Treatment of cells with PDGF prevented protein damage and cell death caused by exposure to the lipid peroxidation product 4-hydroxynonenal. The results of the present study demonstrate a distinct form of autophagy induced by PDGF that is essential for attaining the synthetic phenotype and for survival under the conditions of high oxidative stress found to occur in vascular lesions.
Authors:
Joshua K Salabei; Timothy D Cummins; Mahavir Singh; Steven P Jones; Aruni Bhatnagar; Bradford G Hill
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Biochemical journal     Volume:  451     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-15     Completed Date:  2013-05-31     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  375-88     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Actins / genetics,  metabolism
Adenine / analogs & derivatives,  pharmacology
Aldehydes / pharmacology
Animals
Aorta / cytology,  drug effects*,  metabolism
Autophagy / drug effects*,  genetics
Biological Markers / metabolism
Calcium-Binding Proteins / genetics,  metabolism
Gene Expression Regulation / drug effects*
Macrolides / pharmacology
Male
Microfilament Proteins / genetics,  metabolism
Microtubule-Associated Proteins / genetics,  metabolism
Muscle, Smooth, Vascular / cytology,  drug effects*,  metabolism
Myocytes, Smooth Muscle / cytology,  drug effects*,  metabolism
Osteopontin / genetics,  metabolism
Oxidative Stress
Phenotype
Platelet-Derived Growth Factor / pharmacology
Primary Cell Culture
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects
Vimentin / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
GM103492/GM/NIGMS NIH HHS; HL055477/HL/NHLBI NIH HHS; HL078825/HL/NHLBI NIH HHS; HL083320/HL/NHLBI NIH HHS; HL094419/HL/NHLBI NIH HHS; P01 HL078825/HL/NHLBI NIH HHS; P20 GM103492/GM/NIGMS NIH HHS; P20 RR024489/RR/NCRR NIH HHS; R01 HL055477/HL/NHLBI NIH HHS; R01 HL083320/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Actins; 0/Aldehydes; 0/Biological Markers; 0/Calcium-Binding Proteins; 0/LC3 protein, rat; 0/Macrolides; 0/Microfilament Proteins; 0/Microtubule-Associated Proteins; 0/Platelet-Derived Growth Factor; 0/Spp1 protein, rat; 0/Vimentin; 0/calponin; 0/smooth muscle actin, rat; 106441-73-0/Osteopontin; 116764-51-3/bafilomycin A; 29343-52-0/4-hydroxy-2-nonenal; 5142-23-4/3-methyladenine; JAC85A2161/Adenine
Comments/Corrections

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