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PKA-mediated BMAL1 phosphorylation promotes β1-adrenoceptor autoantibody-induced cardiomyocyte death

Yuan Yuan1, Jiayan Feng1, Lingxia Xue1

  • 1Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan, China.

Iscience
|June 30, 2025
PubMed

Insights

Beta-1 adrenoceptor autoantibody (β1-AA) disrupts the circadian rhythm of the BMAL1 protein in heart cells, causing its accumulation and leading to cardiomyocyte death. This process involves specific phosphorylation of BMAL1.

Area of Science:

  • Cardiovascular Biology
  • Circadian Rhythms
  • Molecular Cardiology

Background:

  • BMAL1 is a key circadian transcription factor regulating cardiovascular homeostasis.
  • The role of beta-1 adrenoceptor autoantibody (β1-AA) in BMAL1 dysregulation and cardiomyocyte death is not fully understood.

Purpose of the Study:

  • To investigate the mechanism by which β1-AA induces cardiomyocyte death, focusing on BMAL1 phosphorylation.
  • To elucidate the role of BMAL1 phosphorylation in the context of β1-AA-induced cardiovascular effects.

Main Methods:

  • Analysis of BMAL1 expression and phosphorylation in myocardial tissue and H9c2 cells exposed to β1-AA.
  • Utilizing Bmal1 knockdown and a dephosphorylation-mimic BMAL1 mutant (S42A).
  • Investigating the involvement of Protein Kinase A (PKA) in the observed phosphorylation events.

Main Results:

  • β1-AA disrupted BMAL1 rhythmic expression and upregulated it at CT8.
  • β1-AA increased BMAL1 phosphorylation at Ser42, causing cytoplasmic accumulation.
  • The S42A mutant attenuated β1-AA-induced effects on BMAL1 localization, Per2/Nr1d1 expression, and cell viability.
  • Inhibition of PKA reversed BMAL1 phosphorylation.

Conclusions:

  • β1-AA induces cardiomyocyte death by promoting BMAL1 phosphorylation at Ser42 through PKA activation.
  • Phosphorylated BMAL1 accumulates in the cytoplasm, suppressing Per2 and Nr1d1 transcription.
  • This mechanism highlights a novel pathway linking autoimmune responses to circadian disruption and heart cell death.

Keywords:
Cardiovascular medicineCell biology

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