Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-β1/Smad3 Pathway

Oct 22, 2015Cardiovascular toxicology

Notch3 may reduce heart scarring after a heart attack by blocking the TGF-β1/Smad3 signaling pathway

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Abstract

Notch3 cDNA treatment attenuated cardiac damage and inhibited fibrosis in mice with myocardial infarction.

Notch3 signaling is associated with reduced cardiac fibrosis and improved cardiac function following myocardial infarction.
Administration of Notch3 siRNA worsened cardiac damage and increased fibrosis in the same model.
Notch3 overexpression inhibited the transition of cardiac fibroblasts to myofibroblasts induced by TGF-β1.
Key fibrotic proteins, including a-smooth muscle actin and Type I collagen, were down-regulated with Notch3 overexpression in cardiac fibroblast cells.
Notch3 treatment led to increased levels of MMP-9 and decreased levels of TIMP-2 in TGF-β1-stimulated cardiac fibroblasts.

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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.

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Notch3 Ameliorates Cardiac Fibrosis After Myocardial Infarction by Inhibiting the TGF-β1/Smad3 Pathway

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