PKA-mediated BMAL1 phosphorylation promotes β-adrenoceptor autoantibody-induced cardiomyocyte death.

As a core circadian transcription factor, BMAL1 orchestrates cardiovascular homeostasis. However, whether β-adrenoceptor autoantibody (β-AA) promotes abnormal BMAL1 expression and accelerates cardiomyocyte death remains unclear. This study reveals the role and mechanism of BMAL1 phosphorylation in cardiomyocyte death induced by β-AA. We demonstrated that β-AA disrupted the rhythmic expression of BMAL1 in myocardial tissue and H9c2 cells, specifically upregulating BMAL1 at CT8. knockdown did not reverse the β-AA-induced reduction in cell viability. Furthermore, β-AA increased BMAL1 phosphorylation at Ser42, leading to its cytoplasmic accumulation. The dephosphorylation-mimic BMAL1 mutant (S42A) significantly alleviated the upregulation of cytoplasmic BMAL1, the downregulation of and mRNA levels, and the reduction in cell viability induced by β-AA. Additionally, BMAL1 phosphorylation was reversed by inhibiting PKA activity. These findings indicate that β-AA promotes BMAL1 phosphorylation at Ser42 via PKA activation, resulting in cytoplasmic accumulation of BMAL1, suppression of and transcription, and ultimately cardiomyocyte death.