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Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-β1/Smad3 Pathway
- Source :
- Cardiovascular Toxicology. 16:316-324
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Notch3 and TGF-β1 signaling play a key role in the pathogenesis and progression of chronic cardiovascular disease. However, whether Notch3 protects against myocardial infarction (MI) and the underlying mechanisms remains unknown. C57BL/6 mice were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) before coronary artery ligation. Four weeks after constructing MI model, cardiac function and fibrosis were compared between groups. The cardiac fibroblast cells (CFs) were isolated from newborn C57BL/6 mice (1-3 days old) and transfected with lentivirus carrying Notch3 cDNA. TGF-β1 (5 ng/ml), a well-known pro-fibrotic factor, was administered 72 h after Notch3 cDNA administration in CFs. The related proteins of fibrosis such as a-smooth muscle actin (a-SMA), Type I collagen, metalloprotease (MMP)-9 and the tissue inhibitor of metalloproteinases (TIMP)-2 were examined by western blot analysis. Notch3 cDNA treatment attenuated cardiac damage and inhibited fibrosis in mice with MI. Meanwhile, Notch3 siRNA administration aggravated cardiac function damage and markedly enhanced cardiac fibrosis in mice with MI. Overexpression of Notch3 inhibited TGF-β1-induced fibroblast-myofibroblast transition of mouse cardiac fibroblast cells, as evidenced by down-regulating a-SMA and Type I collagen expression. Notch3 cDNA treatment also increased MMP-9 expression and decreased TIMP-2 expression in the TGF-β1-stimulated cells. This study indicates that Notch3 is an important protective factor for cardiac fibrosis in a MI model, and the protective effect of Notch3 is attributable to its action on TGF-β1/Smad3 signaling.
- Subjects :
- Male
0301 basic medicine
Cardiac function curve
Pathology
medicine.medical_specialty
Time Factors
Cardiac fibrosis
Myocardial Infarction
030204 cardiovascular system & hematology
Transfection
Toxicology
Collagen Type I
Ventricular Function, Left
Transforming Growth Factor beta1
Pathogenesis
03 medical and health sciences
0302 clinical medicine
Western blot
Fibrosis
medicine
Animals
Smad3 Protein
Myocardial infarction
Myofibroblasts
Receptor, Notch3
Molecular Biology
Cells, Cultured
Tissue Inhibitor of Metalloproteinase-2
medicine.diagnostic_test
business.industry
Myocardium
Fibroblasts
medicine.disease
Actins
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Matrix Metalloproteinase 9
Cancer research
RNA Interference
Cardiology and Cardiovascular Medicine
business
Type I collagen
Signal Transduction
Subjects
Details
- ISSN :
- 15590259 and 15307905
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Toxicology
- Accession number :
- edsair.doi.dedup.....a1fd08a38de6a45917d69ae7ba33b820