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Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells
- Source :
- American Journal of Physiology-Heart and Circulatory Physiology. 309:H1075-H1086
- Publication Year :
- 2015
- Publisher :
- American Physiological Society, 2015.
-
Abstract
- Although degradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be involved in symptomatic (S) carotid plaques in atherosclerosis, the mechanisms of MMP expression are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from S plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. Inhibitors of p38-MAPK and JNK-MAPK signaling pathways downregulated the expression of MMP-1 and MMP-9. In addition, we examined whether v-ets erythroblastosis virus E26 oncogene homologue 1 (Ets-1), an important regulator of different genes, is involved in destabilizing S plaques in patients with carotid stenosis. We demonstrate that EGF induces Ets-1 expression and decreases interstitial and basement membrane collagen in vascular smooth muscle cells (VSMCs) from patients with carotid stenosis. Increased expression of MMP-1 and -9 and decreased collagen mRNA transcripts were also found in Ets-1-overexpressed VSMCs. Transfection with both dominant-negative form of Ets-1 and small interfering RNA blocked EGF-induced MMP-1 and -9 expressions and increased the mRNA transcripts for collagen I (α1) and collagen III (α1) in S compared with asymptomatic (AS) carotid plaques. Inhibitors of p38-MAPK (SB202190) and JNK-MAPK (SP600125) signaling pathways decreased the expression of Ets-1, MMP-1, and MMP-9 and increased collagen type I and III expression in EGF-treated VSMCs. This study provides a mechanistic insight into the role of Ets-1 in the plaque destabilization in patients with carotid stenosis involving p38-MAPK and JNK signaling pathways.
- Subjects :
- Male
Small interfering RNA
medicine.medical_specialty
Vascular smooth muscle
MAP Kinase Signaling System
Physiology
Myocytes, Smooth Muscle
Cell Culture Techniques
Matrix metalloproteinase
Biology
p38 Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular
Proto-Oncogene Protein c-ets-1
Extracellular matrix
Phosphatidylinositol 3-Kinases
Integrative Cardiovascular Physiology and Pathophysiology
Epidermal growth factor
Physiology (medical)
Internal medicine
medicine
Humans
Myocyte
Carotid Stenosis
RNA, Messenger
Aged
Basement membrane
Epidermal Growth Factor
Reverse Transcriptase Polymerase Chain Reaction
Middle Aged
Cell biology
medicine.anatomical_structure
Endocrinology
Gene Expression Regulation
Matrix Metalloproteinase 9
Female
Collagen
Matrix Metalloproteinase 1
Signal transduction
Cardiology and Cardiovascular Medicine
Signal Transduction
Subjects
Details
- ISSN :
- 15221539 and 03636135
- Volume :
- 309
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Heart and Circulatory Physiology
- Accession number :
- edsair.doi.dedup.....ac1fc185673b3eaa33e1e0d70d0d6ff7