ZBP1 Protects Against mtDNA-Induced Myocardial Inflammation in Failing Hearts

Area of Science:

• Cardiology
• Immunology
• Molecular Biology

Background:

• Mitochondrial DNA (mtDNA) triggers myocardial inflammation and cardiac remodeling.
• Z-DNA binding protein 1 (ZBP1) is a known regulator of inflammation in response to mtDNA.
• The specific role of ZBP1 in heart inflammation and remodeling was previously unclear.

Purpose of the Study:

• To investigate the role of ZBP1 in mitochondrial DNA-induced inflammation within cardiomyocytes.
• To elucidate the function of ZBP1 in the context of failing hearts and cardiac remodeling.

Main Methods:

• Administered mtDNA to isolated cardiomyocytes.
• Induced myocardial infarction in wild-type and ZBP1 knockout mice.

Main Results:

• ZBP1 knockdown exacerbated mtDNA-induced inflammation (IL-1β, IL-6) and associated signaling pathways (RIPK3, NF-κB, NLRP3) in cardiomyocytes.
• ZBP1 knockout mice showed worsened cardiac dysfunction, dilatation, fibrosis, and apoptosis post-myocardial infarction.
• Increased cytosolic mtDNA (D-loop) and inflammatory markers (ZBP1, RIPK3, NF-κB, NLRP3, IL-1β, IL-6) were observed in failing hearts.

Conclusions:

• ZBP1 acts as an endogenous suppressor of mtDNA-induced myocardial inflammation.
• ZBP1 plays a protective role against cardiac remodeling.
• Targeting ZBP1 may offer therapeutic potential for inflammatory heart conditions.