Fibroblast Smad7 Induction Protects the Remodeling Pressure-Overloaded Heart

Area of Science:

• Cardiovascular Biology
• Fibrosis Research
• Molecular Cardiology

Background:

• Cardiac fibroblast activation drives adverse remodeling and fibrosis in pressure-overloaded hearts.
• Sustained transforming growth factor-β (TGF-β) signaling exacerbates fibrosis and dysfunction.
• Endogenous mechanisms regulating TGF-β response in fibroblasts are crucial for preventing progressive cardiac damage.

Purpose of the Study:

• To investigate the role of Smad7, an inhibitory Smad, in regulating cardiac fibrosis and remodeling.
• To test the hypothesis that Smad7 is induced in pressure-overloaded hearts and modulates TGF-β signaling.
• To determine the impact of myofibroblast-specific Smad7 loss on cardiac function and pathology.

Main Methods:

• Utilized a mouse model of transverse aortic constriction to study myofibroblast-specific Smad7 knockout (MFS7KO) mice.
• Employed echocardiography, histology, and molecular analyses to assess cardiac function and remodeling.
• Conducted proteomic and secretomic analyses in cell cultures and mouse models to identify Smad7-modulated mediators.

Main Results:

• Smad7 was upregulated in cardiac myofibroblasts following pressure overload, induced by TGF-β, angiotensin II, and GDF15.
• MFS7KO mice exhibited increased mortality, exacerbated systolic and diastolic dysfunction, and heightened fibrosis.
• Smad7 loss led to increased matrix metalloproteinase (MMP)-2 activity, collagen denaturation, and enhanced macrophage activation via matricellular proteins.

Conclusions:

• Smad7 exerts antifibrotic effects in pressure-overloaded hearts, protecting against dysfunction.
• Smad7's protective role involves reducing collagen deposition, suppressing MMP2-mediated matrix denaturation, and inhibiting macrophage activation.
• Targeting Smad7 represents a potential therapeutic strategy for mitigating adverse cardiac remodeling and fibrosis.