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Modulation of NOX2 causes obesity-mediated atrial fibrillation

Arvind Sridhar1,2, Jaime DeSantiago1, Hanna Chen1

  • 1Division of Cardiology.

The Journal of Clinical Investigation
|August 15, 2024
PubMed

Insights

Obesity increases atrial fibrillation (AF) risk through oxidative stress. Inhibiting NADPH oxidase 2 (NOX2) reduced AF in obese mice and cells by normalizing ion channels and PITX2 expression.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Obesity is a significant risk factor for atrial fibrillation (AF), often mediated by increased oxidative stress.
  • NADPH oxidase 2 (NOX2) is a key source of reactive oxygen species (ROS) in the heart, implicated in AF pathogenesis, but its precise role in obesity-related AF is not fully understood.

Purpose of the Study:

  • To investigate the role of NOX2-mediated ROS production in obesity-induced AF.
  • To elucidate the molecular mechanisms linking NOX2, oxidative stress, and AF in obesity.

Main Methods:

  • Utilized diet-induced obesity (DIO) mouse models and human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs).
  • Administered NOX blocker (apocynin) to DIO mice and a NOX2-specific inhibitor to PA-treated hiPSC-aCMs.
  • Performed transcriptomics analysis and used hydrogen peroxide as a NOX2 surrogate.

Main Results:

  • NOX2 inhibition normalized atrial action potential duration and reversed obesity-associated ion channel remodeling, reducing AF burden.
  • Transcriptomics revealed NOX2 upregulates paired-like homeodomain transcription factor 2 (PITX2) in obesity-mediated AF.
  • Increased NOX2-derived ROS directly correlated with elevated PITX2 expression in hiPSC-aCMs.

Conclusions:

  • NOX2-mediated ROS production and subsequent PITX2 upregulation are key mechanisms in obesity-related atrial remodeling and AF.
  • NOX2 inhibition presents a potential therapeutic strategy for managing obesity-associated AF.
Keywords:
ArrhythmiasCardiology

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