Chronic treatment with PDGF-BB and endothelin-1 synergistically induces vascular hyperplasia and loss of contractility in organ-cultured rat tail artery

Autor: Shigeko Matsumoto, Hiroshi Ozaki, Masatoshi Hori, Takahisa Murata, Hideyuki Yamawaki, Taiki Kida, Hiroko Chuma
Rok vydání: 2009
Předmět:
Male
Vascular smooth muscle
Time Factors
Becaplermin
Muscle
Smooth
Vascular
Ribosomal s6 kinase
Rats
Sprague-Dawley
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Vasoconstrictor Agents
LY294002
Phosphorylation
Phosphoinositide-3 Kinase Inhibitors
Mitogen-Activated Protein Kinase 1
Platelet-Derived Growth Factor
Mitogen-Activated Protein Kinase 3
biology
Endothelin-1
TOR Serine-Threonine Kinases
Ribosomal Protein S6 Kinases
70-kDa
Drug Synergism
Arteries
Proto-Oncogene Proteins c-sis
Immunohistochemistry
Recombinant Proteins
Cardiology and Cardiovascular Medicine
Platelet-derived growth factor receptor
Tail
medicine.medical_specialty
Blotting
Western
Myocytes
Smooth Muscle
P70-S6 Kinase 1
Contractility
Organ Culture Techniques
Internal medicine
medicine
Animals
Humans
Protein kinase B
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Cell Proliferation
Hyperplasia
Dose-Response Relationship
Drug
Rats
Endocrinology
chemistry
Vasoconstriction
biology.protein
Proto-Oncogene Proteins c-akt
Zdroj: Atherosclerosis. 214(2)
ISSN: 1879-1484
Popis: Objective In this study, we examined the synergistic effects of the two potent pathogenic factors, platelet-derived growth factor-BB (PDGF-BB) and endothelin-1 (ET-1) to induce vascular hyperplasia using ex vivo organ-culture system. Methods and results In organ-cultured rat tail arteries, concomitant treatment with 100ng/ml PDGF-BB and 300nM ET-1 for 4 days induced medial hyperplasia with increased smooth muscle cell proliferation. Concomitant treatment with PDGF-BB (10–300nM) and ET-1 (30nM–1μM) dose-dependently suppressed contractile responses to high K + and norepinephrine. This dyscontractility was accompanied by decreased α-actin protein expression. In all series of experiments, concomitant treatment with PDGF-BB and ET-1 exhibited stronger effects than sole treatment with PDGF-BB (100ng/ml) or ET-1 (300nM). Western blot analysis revealed that concomitant treatment with PDGF-BB and ET-1 synergistically phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2), Akt, and a downstream target of mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase in cultured artery. Consistently, a MAPK/ERK kinase (MEK) inhibitor, PD98059 (30μM), a phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, and an mTOR inhibitor, rapamycin (30nM), partially restored PDGF-BB and ET-1-induced hyperplastic changes. Conclusions We evidenced for the first time at tissue level that PDGF-BB and ET-1 synergistically accelerate vascular smooth muscle hyperplastic changes and lose its contractility, at least partially through ERK1/2, Akt, and mTOR activation.
Databáze: OpenAIRE
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