Scleraxis and fibrosis in the pressure-overloaded heart

Area of Science:

• Cardiovascular Biology
• Fibrosis Research
• Molecular Cardiology

Background:

• Scleraxis (Scx) regulates cardiac fibroblast activation in vitro.
• The in vivo role of scleraxis in cardiac fibrosis remains unknown.
• Cardiac fibrosis is a key driver of heart failure progression.

Purpose of the Study:

• To investigate the role of scleraxis in fibroblast activation, cardiac fibrosis, and dysfunction in pressure overload-induced heart failure.
• To assess the therapeutic potential of targeting scleraxis for anti-fibrotic treatments.

Main Methods:

• Utilized a tamoxifen-inducible fibroblast-specific scleraxis knockout (Scx-fKO) mouse model.
• Induced pressure overload heart failure using transverse aortic constriction (TAC).
• Assessed cardiac fibrosis, fibroblast activation, cardiac function, and survival post-TAC.

Main Results:

• Scleraxis expression was upregulated in human heart failure and in TAC mice.
• Scx-fKO mice exhibited completely attenuated cardiac fibrosis and improved systolic function and ventricular remodeling after TAC.
• Scleraxis deletion reduced mortality, attenuated fibroblast activation and myofibroblast markers like periostin, and improved function even after fibrosis was established.

Conclusions:

• Scleraxis is a critical regulator of fibroblast activation and cardiac fibrosis in pressure overload-induced heart failure.
• Targeting scleraxis presents a promising strategy for developing novel anti-fibrotic therapies.
• Scleraxis knockout significantly improves cardiac function and survival in a heart failure model.