P300/CBP-Associated Factor Activates Cardiac Fibroblasts by SMAD2 Acetylation

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Molecular Medicine

Background:

• Cardiac remodeling and fibrosis are detrimental consequences of heart disease, leading to impaired heart function.
• Myofibroblast activation is a critical process in cardiac fibrosis.
• The role of histone acetyltransferases, like PCAF, in cardiac fibroblast activation remains unclear.

Purpose of the Study:

• To investigate the role of p300/CBP-associated factor (PCAF) in cardiac fibroblast activation and cardiac fibrosis.
• To elucidate the molecular mechanisms by which PCAF influences fibrosis-related signaling pathways.

Main Methods:

• In vivo studies using isoproterenol (ISP)-induced cardiac fibrosis in mice.
• In vitro studies with human cardiac fibroblast cells treated with transforming growth factor-β1 (TGF-β1).
• Utilized PCAF small interfering RNA (siRNA) to inhibit PCAF activity and assessed effects on fibrosis markers, cell behavior, and SMAD2 signaling.

Main Results:

• ISP injection induced cardiac fibrosis and altered PCAF levels and activity in cardiac fibroblasts.
• TGF-β1 treatment in vitro modulated PCAF activity and mimicked in vivo findings.
• PCAF inhibition via siRNA attenuated TGF-β1-induced fibrosis markers, cell contraction, migration, and SMAD2 phosphorylation/nuclear localization.
• PCAF was found to directly interact with and acetylate SMAD2.

Conclusions:

• Increased PCAF activity is implicated in the development of cardiac fibrosis.
• PCAF activation contributes to cardiac fibroblast activation and myofibroblast differentiation.
• PCAF may promote cardiac fibrosis by acetylating and activating SMAD2, a key signaling molecule.