DNA single-strand break-induced DNA damage response causes heart failure

Area of Science:

• Cardiovascular Biology
• Genomics and Molecular Biology
• Cellular Stress Response

Background:

• The DNA damage response (DDR) is crucial for genome stability.
• DNA damage and DDR activation occur in heart failure, but the specific damage type and its role are unclear.

Purpose of the Study:

• To investigate the role of DNA single-strand breaks (SSBs) in pressure overload-induced heart failure.
• To elucidate the mechanism by which SSBs contribute to heart failure pathogenesis.

Main Methods:

• Utilized mouse models of pressure overload-induced heart failure.
• Examined SSB accumulation in cardiomyocytes.
• Assessed DDR activation, NF-κB signaling, and inflammatory cytokine expression.
• Investigated the roles of XRCC1 (SSB repair protein) and ATM (DDR kinase).

Main Results:

• Accumulation of unrepaired SSBs was observed in cardiomyocytes of failing hearts.
• Unrepaired SSBs activated DDR and increased inflammatory cytokine expression via NF-κB.
• Mice lacking XRCC1 exhibited more severe heart failure, which was ameliorated by ATM deletion, confirming the causative role of SSB accumulation and DDR activation.
• Pressure overload induced significant DNA damage in cardiomyocytes.

Conclusions:

• DNA single-strand breaks (SSBs) play a critical role in the pathogenesis of pressure overload-induced heart failure.
• SSB accumulation triggers DDR and inflammation, exacerbating cardiac dysfunction.
• Inhibition of SSB accumulation or persistent DDR activation presents a potential therapeutic strategy for heart failure.