Yuan Yuan, Feng Jiayan, Xue Lingxia, Lu Jiebei, Ma Mingxia, Long Yaolin, Li Yang, Wang Xiaohui, Wang Li
Research Institute of Circadian Rhythm and Disease, Shanxi Medical University, Taiyuan, China.
Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Taiyuan, China.
iScience. 2025 May 29;28(7):112786. doi: 10.1016/j.isci.2025.112786. eCollection 2025 Jul 18.
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.
作为一种核心昼夜节律转录因子，BMAL1协调心血管稳态。然而，β-肾上腺素能受体自身抗体（β-AA）是否会促进BMAL1异常表达并加速心肌细胞死亡仍不清楚。本研究揭示了BMAL1磷酸化在β-AA诱导的心肌细胞死亡中的作用和机制。我们证明，β-AA破坏了心肌组织和H9c2细胞中BMAL1的节律性表达，特别是在CT8时特异性上调BMAL1。敲低并没有逆转β-AA诱导的细胞活力降低。此外，β-AA增加了BMAL1在Ser42处的磷酸化，导致其在细胞质中积累。模拟去磷酸化的BMAL1突变体（S42A）显著减轻了β-AA诱导的细胞质BMAL1上调、和mRNA水平下调以及细胞活力降低。此外，通过抑制PKA活性可逆转BMAL1磷酸化。这些发现表明，β-AA通过激活PKA促进BMAL1在Ser42处的磷酸化，导致BMAL1在细胞质中积累，抑制和转录，并最终导致心肌细胞死亡。
