PDGF-mediated autophagy regulates vascular smooth muscle cell phenotype and resistance to oxidative stress

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...

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Vydané v:Biochemical journal Ročník 451; číslo 3; s. 375
Hlavní autori: Salabei, Joshua K, Cummins, Timothy D, Singh, Mahavir, Jones, Steven P, Bhatnagar, Aruni, Hill, Bradford G
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: England 01.05.2013
Predmet:
Actins - genetics
Actins - metabolism
Adenine - analogs & derivatives
Adenine - pharmacology
Aldehydes - pharmacology
Animals
Aorta - cytology
Aorta - drug effects
Aorta - metabolism
Autophagy - drug effects
Autophagy - genetics
Biomarkers - metabolism
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Calponins
Gene Expression Regulation - drug effects
Macrolides - pharmacology
Male
Microfilament Proteins - genetics
Microfilament Proteins - metabolism
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - metabolism
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Osteopontin - genetics
Osteopontin - metabolism
Oxidative Stress
Phenotype
Platelet-Derived Growth Factor - pharmacology
Primary Cell Culture
Rats
Rats, Sprague-Dawley
Signal Transduction - drug effects
Vimentin - genetics
Vimentin - metabolism
ISSN:1470-8728, 1470-8728
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Popis
Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1470-8728
1470-8728
DOI:10.1042/BJ20121344