HDAC5 catalytic activity suppresses cardiomyocyte oxidative stress and NRF2 target gene expression

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Redox Homeostasis

Background:

• Class IIa histone deacetylases (HDAC5 and HDAC9) repress pathological cardiomyocyte hypertrophy.
• The role of catalytic activity of class IIa HDACs in the heart is largely unknown.
• HDAC5 and HDAC9 catalytic domains are not essential for inhibiting cardiac hypertrophy.

Purpose of the Study:

• To investigate the function of catalytic activity of class IIa HDACs in cardiomyocytes.
• To determine the role of HDAC5 catalytic activity in regulating oxidative stress and antioxidant responses.
• To explore the therapeutic potential of class IIa HDAC inhibitors.

Main Methods:

• Utilized selective class IIa HDAC inhibitors (TMP195, TMP269).
• Employed shRNA-mediated knockdown of HDAC5 and HDAC9.
• Assessed mitochondrial reactive oxygen species generation and NRF2-dependent gene expression.
• Examined effects of ectopic expression of catalytically active HDAC5.

Main Results:

• Catalytic activity of HDAC5, not HDAC9, suppresses mitochondrial reactive oxygen species (ROS) production.
• HDAC5 catalytic activity inhibits the induction of NF-E2-related factor 2 (NRF2)-dependent antioxidant genes.
• Class IIa HDAC inhibitors (TMP195, TMP269) and HDAC5 knockdown stimulate NRF2 transcription in a ROS-dependent manner.
• Active HDAC5 reduces cardiomyocyte oxidative stress and NRF2 activation.

Conclusions:

• HDAC5's catalytic domain plays a crucial role in controlling cardiomyocyte redox homeostasis.
• TMP195 and TMP269 are novel NRF2 activators that function by inhibiting HDAC5 enzymatic activity.
• Targeting HDAC5 offers a potential therapeutic strategy for conditions involving oxidative stress in the heart.