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<p>Heart failure is associated with myocardial fibrosis, a pivotal histopathological feature arising from β-adrenergic receptor (β-AR) stimulation through sympathetic nervous system activation. Augmented glutaminolysis with increased bioavailability of α-ketoglutarate (α-KG) is suggested to contribute to fibrogenesis and changes in cellular gene expression. K<sub>Ca</sub>3.1 is a calcium-activated potassium channel expressed in fibroblasts and has been implicated in mediating fibrosis, yet the putative interactions between glutaminolysis and K<sub>Ca</sub>3.1 in β-AR-mediated cardiac fibrosis remain poorly understood. Here, we performed a series of <i>in vitro</i> and <i>in vivo</i> experiments to investigate how α-KG might influence the expression of K<sub>Ca</sub>3.1 in the context of experimental myocardial fibrosis driven by β-AR activation. In cultured adult mouse cardiac fibroblasts, α-KG exposure resulted in the upregulation of K<sub>Ca</sub>3.1 mRNA and protein levels that were commensurate with the dose and duration of exposure, and also led to increased K<sub>Ca</sub>3.1 channel currents. Exposure to α-KG led to a significant decrease in levels of histone methylation (H3K27me3) within the K<sub>Ca</sub>3.1 promoter, a decrease in the association of the transcription repressor REST from this site, as well as an enrichment of transcription activator AP-1 binding. The exacerbated fibrotic signaling induced by α-KG in cultured fibroblasts was suppressed by functional inhibition of K<sub>Ca</sub>3.1 or by genetic knockdown of <i>Kcnn4</i>. Moreover, β-AR activation by isoproterenol significantly augmented glutaminolysis mediated by glutaminase 1 (GLS1) and significantly increased α-KG levels detected in the supernatant of cultured fibroblasts and cardiomyocytes. In addition, isoproterenol-induced K<sub>Ca</sub>3.1 expression in fibroblasts was curtailed by treatment with the GLS1 inhibitor CB-839, or by GLS1 gene knockdown, or by treatment with the selective β<sub>2</sub>-AR antagonist, ICI118551. In mouse models of established cardiac fibrosis evoked by isoproterenol-stimulation or β<sub>2</sub>-AR overexpression, treatment with CB-839 for 4 weeks suppressed the phenotypic features of fibrosis, and this was associated with a decline in α-KG tissue content, a lack of histone demethylation at the K<sub>Ca</sub>3.1 promoter, as well as suppression of K<sub>Ca</sub>3.1 expression. Taken together, our study demonstrates for the first time that glutaminolysis contributes to β-AR activation-induced myocardial fibrosis via α-KG-stimulated K<sub>Ca</sub>3.1 expression. We anticipate that treatments which target the β-AR/GLS1/α-KG/K<sub>Ca</sub>3.1 signaling pathway might be effective for cardiac fibrosis.</p>

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Glutaminolysis and α-ketoglutarate-stimulated KCa3.1 expression contribute to β-adrenoceptor activation-induced myocardial fibrosis in mice

  • 期刊论文

  • 发表日期：

    2025年5月7日

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  • Ru-Yue Bai,
  • Lin-Hong Wu,
  • Yan Wang,
  • Chen Guo,
  • Gang She,
  • Zheng-Da Pang,
  • Jing-Jing Li,
  • Xin-Yi Zhao,
  • Meng-Zhuan Han,
  • Xia-Xia Hai,
  • Yi-Yi Yang,
  • Yi Zhang,
  • Li-Mei Zhao,
  • Lian-Ying Jiao,
  • Xiao-Jun Du,
  • Xiu-Ling Deng

摘要

Heart failure is associated with myocardial fibrosis, a pivotal histopathological feature arising from β-adrenergic receptor (β-AR) stimulation through sympathetic nervous system activation. Augmented glutaminolysis with increased bioavailability of α-ketoglutarate (α-KG) is suggested to contribute to fibrogenesis and changes in cellular gene expression. KCa3.1 is a calcium-activated potassium channel expressed in fibroblasts and has been implicated in mediating fibrosis, yet the putative interactions between glutaminolysis and KCa3.1 in β-AR-mediated cardiac fibrosis remain poorly understood. Here, we performed a series of in vitro and in vivo experiments to investigate how α-KG might influence the expression of KCa3.1 in the context of experimental myocardial fibrosis driven by β-AR activation. In cultured adult mouse cardiac fibroblasts, α-KG exposure resulted in the upregulation of KCa3.1 mRNA and protein levels that were commensurate with the dose and duration of exposure, and also led to increased KCa3.1 channel currents. Exposure to α-KG led to a significant decrease in levels of histone methylation (H3K27me3) within the KCa3.1 promoter, a decrease in the association of the transcription repressor REST from this site, as well as an enrichment of transcription activator AP-1 binding. The exacerbated fibrotic signaling induced by α-KG in cultured fibroblasts was suppressed by functional inhibition of KCa3.1 or by genetic knockdown of Kcnn4. Moreover, β-AR activation by isoproterenol significantly augmented glutaminolysis mediated by glutaminase 1 (GLS1) and significantly increased α-KG levels detected in the supernatant of cultured fibroblasts and cardiomyocytes. In addition, isoproterenol-induced KCa3.1 expression in fibroblasts was curtailed by treatment with the GLS1 inhibitor CB-839, or by GLS1 gene knockdown, or by treatment with the selective β2-AR antagonist, ICI118551. In mouse models of established cardiac fibrosis evoked by isoproterenol-stimulation or β2-AR overexpression, treatment with CB-839 for 4 weeks suppressed the phenotypic features of fibrosis, and this was associated with a decline in α-KG tissue content, a lack of histone demethylation at the KCa3.1 promoter, as well as suppression of KCa3.1 expression. Taken together, our study demonstrates for the first time that glutaminolysis contributes to β-AR activation-induced myocardial fibrosis via α-KG-stimulated KCa3.1 expression. We anticipate that treatments which target the β-AR/GLS1/α-KG/KCa3.1 signaling pathway might be effective for cardiac fibrosis.