C/EBP-β-mediated upregulation of Ca_V1.2 calcium channel increases arterial constriction in mice with ibrutinib-associated hypertension

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Abstract

Ibrutinib, a Bruton's tyrosine kinase inhibitor, is indicated for treating chronic lymphocytic leukemia (CLL), but hypertension is a common cardiovascular adverse event. Previous studies have linked ibrutinib to cardiac events through dysregulated intracellular calcium handling, but the mechanisms underlying ibrutinib-associated hypertension remain largely unknown. Here, we followed up 225 CLL patients receiving ibrutinib or managed with watch-and-wait strategy, and identified ibrutinib as an independent risk factor for hypertension. In mice, ibrutinib elevated arterial blood pressure (BP) without structural remodeling of small arteries, and it potentiated K+-induced vasoconstriction. In vascular smooth muscle cells (VSMCs), ibrutinib upregulated CaV1.2 channel expression and function, as evidenced by enhanced CaV1.2 currents and K+-triggered-[Ca2+]i elevation. Mechanistically, ibrutinib suppressed casein kinase 2 (CK2)-mediated HSP90β phosphorylation, and stabilized C/EBP-β, which bound to the promoter of Cacna1c gene and drove CaV1.2 transcription. Significantly, C/EBP-β knockdown attenuated ibrutinib-induced CaV1.2 hyperactivity and vasoconstriction. Collectively, these findings reveal a CK2-HSP90β-C/EBP-β-CaV1.2 signaling cascade through which ibrutinib enhances vascular Ca2+ influx and vasoconstriction, thereby elevating arterial BP. Thus, this study nominates C/EBP-β as a therapeutic target for ibrutinib-associated hypertension.

Authors

Ludan Zhang, Shumin Yin, Wei Hou, Dan Yang, Yiyuan Jia, Yun Liu, Yan Wang, Sirui Zhao, Xiaoyan Gao, Xiaolin Sun, Xiao Lu, Jianyong Li, Ming Chu, Xiaoqing Xiong, Huayuan Zhu, Juejin Wang